Matthew Paul Gleeson

 

แมทธิว พอล กลีสัน

Staff ID
Position Lecture in Physical Chemistry
Room Chemistry Building, Room 501
Phone +662-562-5555 ext. 2163
Fax +662-579-3955, +662-579-0658
Email paul.gleeson@ku.ac.th

Education Qualifications

 


Research Interests

Honors and Awards

 


  1. QM/MM investigation of the reaction rates of substrates of 2,3-dimethylmalate lyase: A catabolic protein isolated from Aspergillus niger

    Chotpatiwetchkul, W., Jongkon, N., Hannongbua, S., Gleeson, M.P.

    Journal of Molecular Graphics and Modelling

    Volume 68, Issue , 2016, Pages 29-38

    DOI: 10.1016/j.jmgm.2016.05.010

    Abstract

    Aspergillus niger is an industrially important microorganism used in the production of citric acid. It is a common cause of food spoilage and represents a health issue for patients with compromised immune systems. Recent studies on Aspergillus niger have revealed details on the isocitrate lyase (ICL) superfamily and its role in catabolism, including (2R, 3S)-dimethylmalate lyase (DMML). Members of this and related lyase super families are of considerable interest as potential treatments for bacterial and fungal infections, including Tuberculosis. In our efforts to better understand this class of protein, we investigate the catalytic mechanism of DMML, studying five different substrates and two different active site metals configurations using molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. We show that the predicted barriers to reaction for the substrates show good agreement with the experimental kcat values. This results help to confirm the validity of the proposed mechanism and open up the possibility of developing novel mechanism based inhibitors specifically for this target. © 2016 Elsevier Inc.


  2. Correction: Application of QM/MM and QM methods to investigate histone deacetylase 8

    Gleeson, D., Gleeson, M.P.

    MedChemComm

    Volume 6, Issue 9, 2015, Pages 1699-

    DOI: 10.1039/c5md90040a

    Abstract


  3. Application of QM/MM and QM methods to investigate histone deacetylase 8

    Gleeson, D., Gleeson, M.P.

    MedChemComm

    Volume 6, Issue 3, 2015, Pages 477-485

    DOI: 10.1039/c4md00471j

    Abstract

    Computational chemistry plays an important supporting role in the early stages of drug discovery research. Such methods are not without flaws, however they can be very useful in the development and testing of hypothesises as well as prioritizing aspects of the exploration process. In this paper we discuss some common issues with employing hybrid quantum mechanical/molecular mechanical (QM/MM) methods in certain drug discovery applications. The QM/MM method provides a means to simulate large biological systems for moderate computational cost. We use the method to assess the metalloproteins, human deacetylases (HDACs), which are targets for a variety of medical conditions including neurodegenerative diseases and HIV infection. Metalloproteins in particular are a challenge to simulate using the rapid empirical methods preferred in the pharmaceutical industry. We report the use of a QM/MM scheme of only moderate computational cost to explore the active site as well as its catalytic reaction. We also demonstrate the value of the method over smaller QM clusters and show that the method is capable of describing the kinetic differences associated with replacing Zn2+ with other metal co-factors. This journal is © 2015 The Royal Society of Chemistry.


  4. Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

    Jongkon, N., Chotpatiwetchkul, W., Gleeson, M.P.

    Journal of Physical Chemistry B

    Volume 119, Issue 35, 2015, Pages 11473-11484

    DOI: 10.1021/acs.jpcb.5b04732

    Abstract

    The isocitrate lyase (ICL) superfamily catalyzes the cleavage of the C(2)-C(3) bond of various α-hydroxy acid substrates. Members of the family are found in bacteria, fungi, and plants and include ICL itself, oxaloacetate hydrolase (OAH), 2-methylisocitrate lyase (MICL), and (2R,3S)-dimethylmalate lyase (DMML) among others. ICL and related targets have been the focus of recent studies to treat bacterial and fungal infections, including tuberculosis. The catalytic process by which this family achieves C(2)-C(3) bond breaking is still not clear. Extensive structural studies have been performed on this family, leading to a number of plausible proposals for the catalytic mechanism. In this paper, we have applied quantum mechanical/molecular mechanical (QM/MM) methods to the most recently reported family member, DMML, to assess whether any of the mechanistic proposals offers a clear energetic advantage over the others. Our results suggest that Arg161 is the general base in the reaction and Cys124 is the general acid, giving rise to a rate-determining barrier of approximately 10 kcal/mol. (Graph Presented). © 2015 American Chemical Society.


  5. Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

    Somboon, T., Ochiai, J., Treesuwan, W., Gleeson, M.P., Hannongbua, S., Mori, S.

    Journal of Molecular Graphics and Modelling

    Volume 52, Issue , 2014, Pages 20-29

    DOI: 10.1016/j.jmgm.2014.05.012

    Abstract

    QM cluster and QM/MM protein models have been employed to understand aspects of the reaction mechanism of plant allene oxide synthase (pAOS). In this study we have investigated two reaction mechanisms for pAOS. The standard pAOS mechanism was contrasted with an alternative involving an additional active site molecule which has been shown to facilitate proton coupled electron transfer (PCET) in related systems. Firstly, we found that the results from QM/MM protein model are comparable with those from the QM cluster model, presumably due to the large active site used. Furthermore, the results from the QM cluster model show that the FeIII and FeIV pathways for the standard mechanism have similar energetic and structural properties, indicating that the reaction mechanism may well proceed via both pathways. However, while the PCET process is facilitated by an additional active site bound water in other related families, in pAOS it is not, suggesting this type of process is not general to all closely related family members. © 2014 Elsevier Inc. All rights reserved.


  6. A novel approach to identify molecular binding to the influenza virus H5N1: Screening using molecularly imprinted polymers (MIPs)

    Wangchareansak, T., Thitithanyanont, A., Chuakheaw, D., Gleeson, M.P., Lieberzeit, P.A., Sangma, C.

    MedChemComm

    Volume 5, Issue 5, 2014, Pages 617-621

    DOI: 10.1039/c3md00272a

    Abstract

    In this report we investigate whether a molecularly imprinted polymer (MIP) of an inactivated strain of influenza A H5N1 could be used to help identify molecules capable of binding to, and inhibiting the function of the virus, via either competitive or allosteric mechanisms. Molecules which bind to the virus and induce a conformational change are expected to show reduced binding to the H5N1 specific MIP. Given the importance of molecular recognition in virus replication, such conformational change might also reduce the effectiveness of neuraminidase (N1) for cleaving the sialic groups necessary for virus replication. We show that the method can indeed differentiate between a potent neuraminidase inhibitor, H1 and H5 antibodies, and N1 specific and non-specific monosaccharide substrates. We suggest that such a method could potentially be used in conjunction with traditional biochemical assays to facilitate the identification of molecules functioning via novel modes of action. This journal is © the Partner Organisations 2014.


  7. Insight into HIV-1 reverse transcriptase - Aptamer interaction from molecular dynamics simulations

    Aeksiri, N., Songtawee, N., Gleeson, M.P., Hannongbua, S., Choowongkomon, K.

    Journal of Molecular Modeling

    Volume 20, Issue 8, 2014, Pages -

    DOI: 10.1007/s00894-014-2380-8

    Abstract

    Human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is considered to be one of the key targets for antiviral drug therapy. The emergence of the aptamers as potential inhibitors against HIV-1 reverse transcriptase has attracted the attention of the scientific community because these macromolecules can effectively inhibit HIV-1 RT with between micromolar to picomolar concentrations. However, it is not clear how aptamers interact with HIV-1 RT. We have undertaken a molecular dynamics (MD) study in order to gain a keen insight into the conformational dynamics of HIV-1 RT on the formation of a complex with an aptamer or DNA substrate.We have therefore employed three separate models: apo HIV-1 RT, HIV-1 RT with a bound RNA aptamer, and HIV-1 RT with a bound DNA substrate. The results show that HIV-1 RT complex with an aptamer was more stable than that with DNA substrate. It was found that the aptamer interacted with HIV-1 RT in a fingers-and-thumb-closed conformation, at the bound at the nucleic acid substrate binding site. We identified key residues within the HIV-1 RT-aptamer complex in order to help design, develop, and test a new aptamer based on therapies in the future. © Springer-Verlag 2014.


  8. ZrCl4-promoted facile synthesis of indole derivatives

    Tummatorn, J., Gleeson, M.P., Krajangsri, S., Thongsornkleeb, C., Ruchirawat, S.

    RSC Advances

    Volume 4, Issue 38, 2014, Pages 20048-20052

    DOI: 10.1039/c4ra02158d

    Abstract

    Zirconium(iv) chloride effectively activates nitrogen (N2) extrusion from aryl azidoacrylates followed by annulation to provide the desired indole products in moderate to good yields. The reaction proceeds at low temperature and in short reaction time and is applicable to a variety of substrates. © 2014 the Partner Organisations.


  9. Probing the binding site characteristics of HSA: A combined molecular dynamics and cheminformatics investigation

    Pongprayoon, P., Gleeson, M.P.

    Journal of Molecular Graphics and Modelling

    Volume 54, Issue , 2014, Pages 164-173

    DOI: 10.1016/j.jmgm.2014.10.007

    Abstract

    Human serum albumin is a remarkable protein found in high concentrations in the body. It contains at least seven distinct fatty acid binding sites and two principle sites for drugs. Its primary function is to act as a fatty acid transport system, but it also shows the capacity to bind a diverse range of acidic, neutral and zwitterionic drug molecules. In this paper we investigate the ligand binding selectivity of HSA using cheminformatics analyses and molecular dynamics simulations. We compare and contrast the known ligand binding specificities as obtained from X-ray structural data using PCA, with additional direct analyses of the seven key binding pockets using analyses derived from molecular simulations. We assess both the fatted and defatted states of HSA using 100 ns simulations of the APO and HOLO forms, as well as structures containing one, three and seven myristic acid molecules. We find that differences in fatty acid binding can have a dramatic effect on the flexibility of the protein and also the pocket characteristics. We discuss how the remarkable selectivity of the HSA pockets towards both endogenous fatty acids and exogenous drug molecules is not simply controlled by bulk property effects such as ionization state and lipophilicity. © 2014 Elsevier Inc. All rights reserved.


  10. Skin sensitization prediction using quantum chemical calculations: A theoretical model for the SNAr domain

    Promkatkaew, M., Gleeson, D., Hannongbua, S., Gleeson, M.P.

    Chemical Research in Toxicology

    Volume 27, Issue 1, 2014, Pages 51-60

    DOI: 10.1021/tx400323e

    Abstract

    It is widely accepted that skin sensitization begins with the sensitizer in question forming a covalent adduct with a protein electrophile or nucleophile. We investigate the use of quantum chemical methods in an attempt to rationalize the sensitization potential of chemicals of the SNAr reaction domain. We calculate the full reaction profile for 23 chemicals with experimental sensitization data. For all quantitative measurements, we find that there is a good correlation between the reported pEC3 and the calculated barrier to formation of the low energy product or intermediate (r2 = 0.64, N = 12) and a stronger one when broken down by specific subtype (r2 > 0.9). Using a barrier cutoff of ∼10 kcal/mol allows us to categorize 100% (N = 12) of the sensitizers from the nonsensitizers (N = 11), with just 1 nonsensitizer being mispredicted as a weak sensitizer (9%). This model has an accuracy of ∼96%, with a sensitivity of 100% and a specificity of ∼91%. We find that the kinetic and thermodynamic information provided by the complete profile can help in the rationalization process, giving additional insight into a chemical's potential for skin sensitization. © 2014 American Chemical Society.


  11. Quantitative Structure-Activity Relationship (QSAR) Methods for the Prediction of Substrates, Inhibitors, and Inducers of Metabolic Enzymes

    Phuangsawai, O., Hannongbua, S., Gleeson, M.P.

    Drug Metabolism Prediction

    Volume , Issue , 2014, Pages 319-350

    DOI: 10.1002/9783527673261.ch13

    Abstract

    A wide variety of experimental protocols have been developed to study the interaction of molecules with individual metabolic proteins. As more and more measurements are made and the number and diversity of compounds assessed in a particular assay increase, the viability of generating predictive guides or models becomes more practical. In this chapter, we review key aspects regarding the generation of structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) models based on metabolic-related assay data. We discuss the most frequently used assay types that are modeled, the various statistical methods and descriptors used during QSAR model generation, and what expectations we should have for such predictive methods. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA. All rights reserved.


  12. Elucidating the origin of the esterase activity of human serum albumin using QM/MM calculations

    Phuangsawai, O., Hannongbua, S., Gleeson, M.P.

    Journal of Physical Chemistry B

    Volume 118, Issue 41, 2014, Pages 11886-11894

    DOI: 10.1021/jp506629y

    Abstract

    Human serum albumin (HSA) is a critical transport plasma protein accounting for ∼60% of the total protein content in blood. Remarkably, this protein is also found to display esterase activity. In this study, we apply theoretical studies to elucidate the origin of the esterase-like activity arising from the Sudlow site I. Using MD and QM/MM calculations, we investigate which active site residues are involved in the reaction, and the precise mechanistic sequence of events. Our results suggest Lys199, His242, and Arg257 help give rise to the esterase activity and that the most catalytically efficient active site configuration requires that both Lys199 and Aspirin are in their neutral forms. The abundance of HSA in the body suggests the protein might be a suitable target for the computational guided design of acetyl based pro-drugs of acidic molecules that often displayed limited oral exposure due to their unmasked ionizable substituent. © 2014 American Chemical Society.


  13. Influenza A virus molecularly imprinted polymers and their application in virus sub-type classification

    Wangchareansak, T., Thitithanyanont, A., Chuakheaw, D., Gleeson, M.P., Lieberzeit, P.A., Sangma, C.

    Journal of Materials Chemistry B

    Volume 1, Issue 16, 2013, Pages 2190-2197

    DOI: 10.1039/c3tb00027c

    Abstract

    In this work, we apply a molecular imprinting strategy as a screening protocol for different influenza A subtypes, namely H5N1, H5N3, H1N1, H1N3 and H6N1. Molecularly imprinted polymers for each of these subtypes lead to appreciable sensor characteristics on a quartz crystal microbalance leading to detection limits as low as 105 particles per ml. Selectivity studies indicate that each virus is preferably incorporated by its own MIP. Recognition in most cases is dominated by the neuraminidase residue rather than the hemagglutinin. Multivariate analysis shows that the sensor responses can be correlated with the differences in hemagglutinin and neuraminidase patterns from databases. This allows for virus subtype characterization and thus rapid screening. © 2013 The Royal Society of Chemistry.


  14. Computational study of EGFR inhibition: Molecular dynamics studies on the active and inactive protein conformations

    Songtawee, N., Gleeson, M.P., Choowongkomon, K.

    Journal of Molecular Modeling

    Volume 19, Issue 2, 2013, Pages 497-509

    DOI: 10.1007/s00894-012-1559-0

    Abstract

    The structural diversity observed across protein kinases, resulting in subtly different active site cavities, is highly desirable in the pursuit of selective inhibitors, yet it can also be a hindrance from a structure-based design perspective. An important challenge in structure-based design is to better understand the dynamic nature of protein kinases and the underlying reasons for specific conformational preferences in the presence of different inhibitors. To investigate this issue, we performed molecular dynamics simulation on both the active and inactive wild type epidermal growth factor receptor (EGFR) protein with both type-I and type-II inhibitors. Our goal is to better understand the origin of the two distinct EGFR protein conformations, their dynamic differences, and their relative preference for Type-I inhibitors such as gefitinib and Type-II inhibitors such as lapatinib. We discuss the implications of protein dynamics from a structure-based design perspective. © 2012 Springer-Verlag.


  15. Ring opening polymerization of mannosyl tricyclic orthoesters: Rationalising the stereo and regioselectivity of glycosidic bond formation using quantum chemical calculations

    Boonyarattanakalin, S., Ruchirawat, S., Gleeson, M.P.

    MedChemComm

    Volume 4, Issue 1, 2013, Pages 265-268

    DOI: 10.1039/c2md20178j

    Abstract

    Quantum chemical calculations have been used to assess the physico-chemical origin of the stereo and regio-selectivity of polymerisation reactions of glycosyl tricyclic orthoesters. From the theoretical reaction pathway we find that subtle modulation of steric and electronic effects at the initiation event can dramatically influence the nature of the polymer products. © The Royal Society of Chemistry 2013.


  16. Enhancement of the solubility, thermal stability, and electronic properties of carbon nanotubes functionalized with MEH-PPV: A combined experimental and computational study

    Prajongtat, P., Suramitr, S., Gleeson, M.P., Mitsuke, K., Hannongbua, S.

    Monatshefte fur Chemie

    Volume 144, Issue 7, 2013, Pages 925-935

    DOI: 10.1007/s00706-013-0963-1

    Abstract

    Multi-walled carbon nanotubes (MWCNTs) functionalized with poly[2-methoxy-5-(2′-ethylhexyloxy)-1,4-phenylenevinylene] (MWCNT-f-MEH-PPV) nanocomposites were successfully prepared by employing a "grafting from" approach. The content of the functionalizing MEH-PPV in the composites was observed as 76 wt.%. Compared with pristine MWCNTs (p-MWCNT), the aqueous solubility and thermal stability of the former are significantly enhanced. The effect of covalently and non-covalently functionalized nanotubes on dye-sensitized solar cell performance was also studied. Solar cells were successfully fabricated from isolated MEH-PPV, p-MWCNT/MEH-PPV, and MWCNT-f-MEH-PPV/MEH-PPV counter electrodes. The devices based on a MWCNT-f-MEH-PPV/MEH-PPV counter electrode demonstrated the best photovoltaic performance as observed by higher J SC, V OC, and fill factor (FF) values. The experimental phenomena can be explained by quantum-chemical calculations: Charge transfer from MEH-PPV oligomers to nanotubes is greater when covalently functionalized compared with non-covalently functionalized. This suggests that the improvement in the photovoltaic parameters of the cells containing covalently functionalized nanotubes results not only from the higher concentration present in the nanotube films of the counter electrode, but also from the greater electron delocalization between the oligomers and nanotubes. © 2013 Springer-Verlag Wien.


  17. Synthesis of substituted 2-arylindanes from e -(2-stilbenyl)methanols via lewis acid-mediated cyclization and nucleophililc transfer from trialkylsilyl reagents

    Sarnpitak, P., Trongchit, K., Kostenko, Y., Sathalalai, S., Gleeson, M.P., Ruchirawat, S., Ploypradith, P.

    Journal of Organic Chemistry

    Volume 78, Issue 17, 2013, Pages 8281-8296

    DOI: 10.1021/jo4013755

    Abstract

    A preparative method for the synthesis of functionalized 2-arylindanes has been developed via the Lewis acid-mediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents. The reactions gave the corresponding products in moderate to high yields and diastereoselectivity. The solvent as well as the nucleophile played an important role in determining the type(s) of product arising either from nucleophilic addition (indanes) or loss of a proton β to the indanyl-type carbocations (indenes). Electron-donating groups on the fused aromatic ring (Y and Z = OMe) or the presence of electron-withdrawing groups (NO2) on the nonfused Ar ring facilitate the cyclization. In contrast, the presence of electron-donating groups (OMe) on the nonfused Ar ring impedes the process. In the case of Cl on the nonfused Ar ring, temperature modulates the resonance versus inductive field effects on the overall reaction pathways involving cyclization to form the indanyl-type cation. Quantum chemical calculations supported the intermediacy of the carbocation species and the transfer of hydride from triethylsilane (Nu = H) to the indanyl-type cations to form the trans-1,2-disubstituted indane as the single diastereomer product. © 2013 American Chemical Society.


  18. Insight into the reaction mechanism of cis,cis-muconate lactonizing enzymes: A DFT QM/MM study

    Somboon, T., Gleeson, M.P., Hannongbua, S.

    Journal of Molecular Modeling

    Volume 18, Issue 2, 2012, Pages 525-531

    DOI: 10.1007/s00894-011-1088-2

    Abstract

    MLEs derived from mycobacterium smegmatis and seudomonas fluorescens share ~76% identity and have a very similar arrangement of catalytic residues in their active site configuration. However, while they catalyze the conversion of cis,cis-muconate to the same achiral product, muconolactone, studies in deuterated solvent surprisingly show that the cyclo-isomerization proceeds with the formation of a chiral product. In this paper we discuss the application of DFT QM/MM calculations on both MLEs, to our knowledge the first reported in the literature on this protein. We investigate the proposal that the base involved in the catalytic reaction is the lysine residue found at the end of the 2 nd strand given: (a) that the lysine residue at the end of the 6 th strand is in an apparently equally effective position to catalyze reaction and (b) that the structural related epimerase in-fact achieve their stereo-specific outcomes by relying on either the base from the 2 nd or 6 th strand. © Springer-Verlag 2011.


  19. The challenges involved in modeling toxicity data in silico: A review

    Gleeson, M.P., Modi, S., Bender, A., Marchese Robinson, R.L., Kirchmair, J., Promkatkaew, M., Hannongbua, S., Glen, R.C.

    Current Pharmaceutical Design

    Volume 18, Issue 9, 2012, Pages 1266-1291

    DOI: 10.2174/138161212799436359

    Abstract

    The percentage of failures in late pharmaceutical development due to toxicity has increased dramatically over the last decade or so, resulting in increased demand for new methods to rapidly and reliably predict the toxicity of compounds. In this review we discuss the challenges involved in both the building of in silico models on toxicology endpoints and their practical use in decision making. In particular, we will reflect upon the predictive strength of a number of different in silico models for a range of different endpoints, different approaches used to generate the models or rules, and limitations of the methods and the data used in model generation. Given that there exists no unique definition of a 'good' model, we will furthermore highlight the need to balance model complexity/interpretability with predictability, particularly in light of OECD/REACH guidelines. Special emphasis is put on the data and methods used to generate the in silico toxicology models, and their strengths and weaknesses are discussed. Switching to the applied side, we next review a number of toxicity endpoints, discussing the methods available to predict them and their general level of predictability (which very much depends on the endpoint considered). We conclude that, while in silico toxicology is a valuable tool to drug discovery scientists, much still needs to be done to, firstly, understand more completely the biological mechanisms for toxicity and, secondly, to generate more rapid in vitro models to screen compounds. With this biological understanding, and additional data available, our ability to generate more predictive in silico models should significantly improve in the future. © 2012 Bentham Science Publishers.


  20. Strategies for the generation, validation and application of in silico ADMET models in lead generation and optimization

    Gleeson, M.P., Montanari, D.

    Expert Opinion on Drug Metabolism and Toxicology

    Volume 8, Issue 11, 2012, Pages 1435-1446

    DOI: 10.1517/17425255.2012.711317

    Abstract

    Introduction: The most desirable chemical starting point in drug discovery is a hit or lead with a good overall profile, and where there may be issues; a clear SAR strategy should be identifiable to minimize the issue. Filtering based on drug-likeness concepts are a first step, but more accurate theoretical methods are needed to i) estimate the biological profile of molecule in question and ii) based on the underlying structureactivity relationships used by the model, estimate whether it is likely that the molecule in question can be altered to remove these liabilities. Areas covered: In this paper, the authors discuss the generation of ADMET models and their practical use in decision making. They discuss the issues surrounding data collation, experimental errors, the model assessment and validation steps, as well as the different types of descriptors and statistical models that can be used. This is followed by a discussion on how the model accuracy will dictate when and where it can be used in the drug discovery process. The authors also discuss how models can be developed to more effectively enable multiple parameter optimization. Expert opinion: Models can be applied in lead generation and lead optimization steps to i) rank order a collection of hits, ii) prioritize the experimental assays needed for different hit series, iii) assess the likelihood of resolving a problem that might be present in a particular series in lead optimization and iv) screen a virtual library based on a hit or lead series to assess the impact of diverse structural changes on the predicted properties. © 2012 Informa UK, Ltd.


  21. Evaluating the enthalpic contribution to ligand binding using QM calculations: Effect of methodology on geometries and interaction energies

    Gleeson, D., Tehan, B., Gleeson, M.P., Limtrakul, J.

    Organic and Biomolecular Chemistry

    Volume 10, Issue 35, 2012, Pages 7053-7061

    DOI: 10.1039/c2ob25657f

    Abstract

    As a result of research on ligand efficiency in the pharmaceutical industry, there is greater focus on optimizing the strength of polar interactions within receptors, so that the contribution of overall size and lipophilicity to binding can be decreased. A number of quantum mechanical (QM) methods involving simple probes are available to assess the H-bonding potential of different heterocycles or functional groups. However, in most receptors, multiple features are present, and these have distinct directionality, meaning very minimalist models may not be so ideal to describe the interactions. We describe how the use of gas phase QM models of kinase protein-ligand complex, which can more closely mimic the polar features of the active site region, can prove useful in assessing alterations to a core template, or different substituents. We investigate some practical issues surrounding the use of QM cluster models in structure based design (SBD). These include the choice of the method; semi-empirical, density functional theory or ab-initio, the choice of the basis set, whether to include implicit or explicit solvation, whether BSSE should be included, etc. We find a combination of the M06-2X method and the 6-31G* basis set is sufficiently rapid, and accurate, for the computation of structural and energetic parameters for this system. © 2012 The Royal Society of Chemistry.


  22. Effect of titanium-tetraisopropoxide concentration on the photocatalytic efficiency of nanocrystalline thin films TiO 2 used for the photodegradation of textile dyes

    Fagnern, N., Leotphayakkarat, R., Chawengkijwanich, C., Gleeson, M.P., Koonsaeng, N., Sanguanruang, S.

    Journal of Physics and Chemistry of Solids

    Volume 73, Issue 12, 2012, Pages 1483-1486

    DOI: 10.1016/j.jpcs.2011.12.028

    Abstract

    The photocatalytic activity of nanocrystalline TiO 2 is a result of many factors, including the concentration, surface area, grain distribution and crystal phase. In this study, the effects of the concentration of titanium-tetraisopropoxide (TTIP) on the crystal structure, optical and the structural properties, such as homogeneity, surface area, crystal size, grain size and grain distribution, was studied using the following techniques: X-ray diffraction (XRD), Environment Scanning Electron Microscopy (E-SEM), Brunauer Emmette and Teller analysis (BET), Atomic Force Microscopy (AFM) and UV-vis spectroscopy. The photocatalytic activities of the TiO 2 thin films synthesized for this study were investigated by their ability to decolour an aqueous solution of two common textile dyes: Reactive Blue19 and Reactive Yellow17. © 2012 ElsevierLtd.Allrightsreserved.


  23. In-silico ADME models: A general assessment of their utility in drug discovery applications

    Gleeson, M.P., Hersey, A., Hannongbua, S.

    Current Topics in Medicinal Chemistry

    Volume 11, Issue 4, 2011, Pages 358-381

    DOI: 10.2174/156802611794480927

    Abstract

    ADME prediction is an extremely challenging area as many of the properties we try to predict are a result of multiple physiological processes. In this review we consider how in-silico predictions of ADME processes can be used to help bias medicinal chemistry into more ideal areas of property space, minimizing the number of compounds needed to be synthesized to obtain the required biochemical/physico-chemical profile. While such models are not sufficiently accurate to act as a replacement for in-vivo or in-vitro methods, in-silico methods nevertheless can help us to understand the underlying physico-chemical dependencies of the different ADME properties, and thus can give us inspiration on how to optimize them. Many global in-silico ADME models (i.e generated on large, diverse datasets) have been reported in the literature. In this paper we selectively review representatives from each distinct class and discuss their relative utility in drug discovery. For each ADME parameter, we limit our discussion to the most recent, most predictive or most insightful examples in the literature to highlight the current state of the art. In each case we briefly summarize the different types of models available for each parameter (i.e simple rules, physico-chemical and 3D based QSAR predictions), their overall accuracy and the underlying SAR. We also discuss the utility of the models as related to lead generation and optimization phases of discovery research. © 2011 Bentham Science Publishers Ltd.


  24. Probing the links between in vitro potency, ADMET and physicochemical parameters

    Gleeson, M.P., Hersey, A., Montanari, D., Overington, J.

    Nature Reviews Drug Discovery

    Volume 10, Issue 3, 2011, Pages 197-208

    DOI: 10.1038/nrd3367

    Abstract

    A common underlying assumption in current drug discovery strategies is that compounds with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochemical properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochemical parameters associated with high in vitro potency and those associated with desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50nM on average); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties. © 2011 Macmillan Publishers Limited. All rights reserved.


  25. Molecular dynamics investigation of psalmopeotoxin I. Probing the relationship between 3D structure, anti-malarial activity and thermal stability

    Gleeson, M.P., Deechongkit, S., Ruchirawat, S.

    Journal of Molecular Modeling

    Volume 17, Issue 4, 2011, Pages 769-775

    DOI: 10.1007/s00894-010-0732-6

    Abstract

    PcFK1 is a member of the cysteine knot inhibitor family that displays anti-malarial properties. The naturally occurring molecule is ∼40 amino acids in length and forms a highly constrained 3D structure due to the presence of 3 disulfide and multiple intra-molecular H-bonds. Recent experimental studies on PcFK1 wild-type and mutants, where the cystiene residues of each disulfide bond were mutated into serine residues, suggest that alterations to these structural constraints can give rise to sizeable differences in SAR. To better understand the relationship between the dynamic inhibitor 3D structure, biophysical and biological properties we have performed solution based molecular dynamics calculations over 150ns using the CHARMM forcefield. We have analyzed the theoretical trajectory in a systematic way using principal components analysis, which allows us to identify the correlated nature of the protein loop, turn and sheet movements. We have identified the key molecular motions that give rise to the differing SAR which has helped to more precisely direct our ongoing SAR studies in this important therapeutic area. © 2010 Springer-Verlag.


  26. Application of drug efficiency index in drug discovery: A strategy towards low therapeutic dose

    Montanari, D., Chiarparin, E., Gleeson, M.P., Braggio, S., Longhi, R., Valko, K., Rossi, T.

    Expert Opinion on Drug Discovery

    Volume 6, Issue 9, 2011, Pages 913-920

    DOI: 10.1517/17460441.2011.602968

    Abstract

    Introduction: The ultimate objective of optimizing adsorption, distribution, metabolism and excretion (ADME) parameters in drug discovery is to maximize the unbound concentration at the site of action for a given dose level. This has the added benefit of minimizing the efficacious dose, reducing the potential for attrition related to drug burden and direct organ toxicity. The concept of drug efficiency was formulated as a tool to obtain a balanced profile between target affinity and ADME properties during lead optimization. Areas covered: The authors discuss how it is possible to maximize the in vivo pharmacological potential addressing whether drug efficiency adds value to the decision-making process and whether it is possible to introduce a single optimization parameter, the drug efficiency index (DEI), linking target affinity and ADME properties, as a marker of in vivo efficacy. Expert opinion: In the absence of a clear hypothesis-driven approach at the beginning of the program (i.e., pharmacokineticpharmacodynamic link), the objective to select molecules with a low therapeutic dose is still a major hurdle in drug discovery. The authors believe that a greater strategic focus on mechanistically relevant measures of the determinants of receptor occupancy would help the optimization and selection process. In this respect, the introduction of the DEI, which can be seen as a correction of target affinity by the in vivo pharmacokinetic potential, may help drug discovery to select and promote those molecules with the highest probability to interact with the biological target and with the best balance between target affinity and ADME properties. © 2011 Informa UK, Ltd.


  27. QM methods in structure based design: Utility in probing protein-ligand interactions

    Gleeson, M.P., Hannongbua, S., Gleeson, D.

    Journal of Molecular Graphics and Modelling

    Volume 29, Issue 4, 2010, Pages 507-517

    DOI: 10.1016/j.jmgm.2010.09.012

    Abstract

    Small changes in ligand structure can lead to large unexpected changes in activity yet it is often not possible to rationalize these effects using empirical modeling techniques, suggesting more effective methods are required. In this study we investigate the use of high level QM methods to study the interactions found within protein-ligand complexes as improved understanding of these could help in the design of new, more active molecules. We study aspects of ligand binding in a set of protein ligand complexes containing ligand efficient, fragment-like inhibitors as these structures are often challenging to determine experimentally. To assess the reliability of our theoretical models we compare the MP2/6-31+G** QM results to the original X-ray coordinates and to QM/MM B3LYP/6-31G*//UFF results which we have previously reported. We also contrast these results with data obtained from an analysis of the distribution of comparable interactions found in (a) high resolution kinase complexes (≤1.8 ) from the PDB and (b) more generic, small molecule crystal structures from the CSD. © 2010 Elsevier Inc. All rights reserved.


  28. QM/MM calculations in drug discovery: A useful method for studying binding phenomena?

    Gleeson, M.P., Gleeson, D.

    Journal of Chemical Information and Modeling

    Volume 49, Issue 3, 2009, Pages 670-677

    DOI: 10.1021/ci800419j

    Abstract

    Herein we investigate whether QM/MM could prove useful as a tool to study the often subtle binding phenomena found within pharmaceutical drug discovery programs. The goal of this investigation is to determine whether it is possible to employ high level QM/MM calculations to answer specific questions around a binding event in a cycle time that is aligned with medicinal chemistry synthesis. To this end QM/MM calculations have been performed on four protein kinase-ligand complexes using five different levels of theory, using standard hardware, in an effort to assess their utility. We conclude that the accuracy and turnaround time of such calculations mean they could prove valuable to (1) probe the subtle nature of the interactions within protein active sites, (2) facilitate the interpretation of poorly resolved electron density, and (3) study the impact of substituent changes on the binding conformation or in the assessment of alternate scaffolds. In practice, the successful application of such methods will be limited by the size of the system under investigation, the level of theory used, and whether there is a need for conformational sampling. © 2009 American Chemical Society.


  29. QM/MM as a tool in fragment based drug discovery. A cross-docking, rescoring study of kinase inhibitors

    Gleeson, M.P., Gleeson, D.

    Journal of Chemical Information and Modeling

    Volume 49, Issue 6, 2009, Pages 1437-1448

    DOI: 10.1021/ci900022h

    Abstract

    The use of QM/MM based methods to optimize and rescore GOLD derived cross-docked protein-ligand poses has been investigated using a range of fragment-like kinase inhibitors where experimental data have been reported. Particular emphasis has been placed on rationalizing the potential benefits of the method in the increasingly popular fragment based drug discovery area. The results of this cross-docking, rescoring study on 9 protein ligand complexes suggest that the hybrid QM/MM calculations could prove useful in kinase fragment based drug discovery (FBDD). B3LYP/6-31G**//UFF derived enthalphies allow us to identify the correct X-ray pose from a range of plausible decoys 77% of the time, almost a doubling of the retrieval rate compared to GOLD (44%). In addition, this method provides us with a means to rapidly and accurately generate virtual protein-ligand complexes that will allow a program team to probe the existing interactions between the ligand and protein and search for additional interactions. © 2009 American Chemical Society.


  30. Generation of a set of simple, interpretable ADMET rules of thumb

    Gleeson, M.P.

    Journal of Medicinal Chemistry

    Volume 51, Issue 4, 2008, Pages 817-834

    DOI: 10.1021/jm701122q

    Abstract

    A set of simple, consistent structure-property guides have been determined from an analysis of a number of key ADMET assays run within GSK: solubility, permeability, bioavailability, volume of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using molecular properties that chemists intuitively know how to alter in a molecule, namely, molecular weight, logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the analyses reported herein that almost all ADMET parameters deteriorate with either increasing molecular weight, logP, or both, with ionization state playing either a beneficial or detrimental affect depending on the parameter in question. This study re-emphasizes the need to focus on a lower molecular weight and logP area of physicochemical property space to obtain improved ADMET parameters. © 2008 American Chemical Society.


  31. The importance of the domain of applicability in QSAR modeling

    Weaver, S., Gleeson, M.P.

    Journal of Molecular Graphics and Modelling

    Volume 26, Issue 8, 2008, Pages 1315-1326

    DOI: 10.1016/j.jmgm.2008.01.002

    Abstract

    The domain of applicability is an important concept in quantitative structure activity relationships (QSAR) that allows one to estimate the uncertainty in the prediction of a particular molecule based on how similar it is to the compounds used to build the model. In this paper we discuss this important concept, providing details of the development and application of a method to compute the domain of applicability within model descriptor space and structural space as defined by daylight fingerprints. The importance of the domain of applicability is illustrated using five QSAR models generated on plasma protein binding and P450 inhibition datasets. Such methodologies will be shown to offer us a means to monitor the performance of QSARs over time, providing us both with a way to estimate the accuracy of a given prediction and identify when a model needs to be rebuilt. © 2008 Elsevier Inc. All rights reserved.


  32. Plasma protein binding affinity and its relationship to molecular structure: An in-silico analysis

    Gleeson, M.P.

    Journal of Medicinal Chemistry

    Volume 50, Issue 1, 2007, Pages 101-112

    DOI: 10.1021/jm060981b

    Abstract

    In-silico plasma protein binding (PPB) models have been generated on human and rat in-house datasets, and on a human dataset sourced from the literature. From the results reported herein, it is apparent that models built on datasets relevant to the chemotypes under investigation in lead optimization programs will perform considerably better in this role than those generated on diverse compounds sourced from the literature. The in-house human and rat partial least-squares regression (PLS) models have cross-validated q2 values of 0.53 and 0.42 on the training sets, respectively. On the independent test and validation sets, they display similar predictive ability, with logK prediction errors of ∼0.5 log units. This compares to ∼0.25 log units variability expected for experiment. Given the considerable interspecies PPB differences, the prediction of PPB in one species using measurements in the other is no better than a prediction from an in-silico model generated on that species. © 2007 American Chemical Society.


  33. Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models

    Gleeson, M.P., Davis, A.M., Chohan, K.K., Paine, S.W., Boyer, S., Gavaghan, C.L., Arnby, C.H., Kankkonen, C., Albertson, N.

    Journal of Computer-Aided Molecular Design

    Volume 21, Issue 10-11, 2007, Pages 559-573

    DOI: 10.1007/s10822-007-9139-6

    Abstract

    In-silico models were generated to predict the extent of inhibition of cytochrome P450 isoenzymes using a set of relatively interpretable descriptors in conjunction with partial least squares (PLS) and regression trees (RT). The former was chosen due to the conservative nature of the resultant models built and the latter to more effectively account for any non-linearity between dependent and independent variables. All models are statistically significant and agree with the known SAR and they could be used as a guide to P450 liability through a classification based on the continuous pIC50 prediction given by the model. A compound is classified as having either a high or low P450 liability if the predicted pIC50 is at least one root mean square error (RMSE) from the high/low pIC50 cut-off of 5. If predicted within an RMSE of the cut-off we cannot be confident a compound will be experimentally low or high so an indeterminate classification is given. Hybrid models using bulk descriptors and fragmental descriptors do significantly better in modeling CYP450 inhibition, than bulk property QSAR descriptors alone. © Springer Science+Business Media B.V. 2007.


  34. In silico human and rat Vss quantitative structure-activity relationship models

    Gleeson, M.P., Waters, N.J., Paine, S.W., Davis, A.M.

    Journal of Medicinal Chemistry

    Volume 49, Issue 6, 2006, Pages 1953-1963

    DOI: 10.1021/jm0510070

    Abstract

    We present herein a QSAR tool enabling an entirely in silico prediction of human and rat steady-state volume of distribution (Vss), to be made prior to chemical synthesis, preceding detailed allometric or mechanistic assessment of Vss. Three different statistical methodologies, Bayesian neural networks (BNN), classification and regression trees (CART), and partial least squares (PLS) were employed to model human (N = 199) and rat (N = 2086) data sets. The results in prediction of an independent test set show the human model has an r2 of 0.60 and an rms error in prediction of 0.48. The corresponding rat model has an r2 of 0.53 and an rms error in prediction of 0.37, indicating both models could be very useful in the early stages of the drug discovery process. This is the first reported entirely in silico approach to the prediction of rat and human steady-state volume of distribution. © 2006 American Chemical Society.


  35. Probing the structural and electronic factors affecting the adsorption and reactivity of alkenes in acidic zeolites using DFT calculations and multivariate statistical methods

    Tantanak, D., Limtrakul, J., Gleeson, M.P.

    Journal of Chemical Information and Modeling

    Volume 45, Issue 5, 2005, Pages 1303-1312

    DOI: 10.1021/ci0500583

    Abstract

    Quantum mechanical (QM) cluster calculations have been performed on a model of ZSM-5 at DFT and MP2 levels. We investigated how the adsorption energies and the energetics of alkoxide intermediate formation of six different alkene substrates, ethene, propene, 1-butene, cis/trans butene, and isobutene, vary in this zeolite model. An analysis of the DFT geometric, electronic, and energetic parameters of the zeolite-substrate complexes, transition states, and alkoxide intermediates is performed using principal components analysis (PCA) and partial least squares (PLS). These deliver an insight into the correlated changes that occur between molecular structure and energy along the reaction coordinate between the physisorbed and chemisorbed species within the zeolite. To the best of our knowledge, this is the first occasion multivariate techniques such as PCA or PLS have been employed to profile the changes in electronics, distances, and angles in QM calculations of catalytic systems such as zeolites. We find the calculated adsorption and the alkoxide intermediate energies correlate strongly with the absolute charge on the substrate and the length of the substrate double bond. The transition states' energies are not affected by the zeolite framework as modeled, which explains why they correlate strongly with the gas-phase substrate protonation energy. Our cluster results show that for ethene, propene, 1-butene, and isobutene, the relative energetics associated with the formation of the alkoxide intermediate in ZSM-5 follow the same trends as calculations where the effects of the framework are included. © 2005 American Chemical Society.


  36. Theoretical analysis of peptidyl α-ketoheterocyclic inhibitors of human neutrophil elastase: Insight into the mechanism of inhibition and the application of QM/MM calculations in structure-based drug design

    Gleeson, M.P., Hillier, I.H., Burton, N.A.

    Organic and Biomolecular Chemistry

    Volume 2, Issue 16, 2004, Pages 2275-2280

    DOI: 10.1039/b402399d

    Abstract

    It has been suggested from QSAR data (P. D. Edwards, D. J. Wolanin, D.A. Andisik and M. W. Davis, J. Med. Chem., 1995, 38, 76) that the inhibition of elastase by peptidyl α-ketoheterocyclic inhibitors can occur in two ways, the less potent inhibitors forming a non-bonded Michaelis complex and the more potent set a covalently bonded enzyme-substrate intermediate. We report QM/MM studies of both binding and reactivity that confirm these findings, showing that the activity of the least potent set of inhibitors correlates with the calculated binding energy, and that of the more potent set correlates with the stability of the intermediate. These calculations show that QM/MM methods can be successfully employed to understand complicated structure-activity relationships and might be employed in the design and assessment of new inhibitors.


  37. Prediction of the potency of inhibitors of adenosine deaminase by QM/MM calculations

    Gleeson, M.P., Burton, N.A., Hillier, I.H.

    Chemical Communications

    Volume 9, Issue 17, 2003, Pages 2180-2181

    DOI:

    Abstract

    QM/MM calculations show that the potency of a range of inhibitors of adenosine deaminase correlates with the relative stability of the reaction intermediate at the active site, rather than with the inhibitor binding energy.


  38. Recent advances in quantum mechanical/molecular mechanical calculations of enzyme catalysis: Hydrogen tunnelling in liver alcohol dehydrogenase and inhibition of elastase by α-ketoheterocycles

    Tresadern, G., Faulder, P.F., Gleeson, M.P., Tai, Z., MacKenzie, G., Burton, N.A., Hillier, I.H.

    Theoretical Chemistry Accounts

    Volume 109, Issue 3, 2003, Pages 108-117

    DOI: 10.1007/s00214-002-0416-0

    Abstract

    Hybrid quantum mechanical (QM)/molecular mechanical (MM) calculations are used to study two aspects of enzyme catalysis, Kinetic isotope effects associated with the hydride ion transfer step in the reduction of benzyl alcohol by liver alcohol dehydrogenase are studied by employing variational transition-state theory and optimised multidimensional tunnelling. With the smaller QM region, described at the Hartree-Fock ab initio level, together with a parameterised zinc atom charge, good agreement with experiment is obtained. A comparison is made with the proton transfer in methylamine dehydrogenase. The origin of the large range in pharmacological activity shown by a series of α-ketoheterocycle inhibitors of the serine protease, elastase, is investigated by both force field and QM/MM calculations. Both models point to two different inhibition mechanisms being operative. Initial QM/MM calculations suggest that these are binding, and reaction to form a tetrahedral intermediate, the latter process occurring for only the more potent set of inhibitors.