Gleeson, Duangkamol

Preferred name

Gleeson, Duangkamol

Main Affiliation

School of Science

duangkamol.gl@kmitl.ac.th

Now showing 1 - 10 of 34

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Evaluating the enthalpic contribution to ligand binding using QM calculations: Effect of methodology on geometries and interaction energies
(2012-09-21)
Gleeson, Duangkamol
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Tehan, Ben
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Gleeson, M. Paul
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Limtrakul, Jumras
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.
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A theoretical study of cis-trans isomerisation in H-ZSM5: Probing the impact of cluster size and zeolite framework on energetics and structure
(2008-01-01)
Gleeson, Duangkamol
In this study the results from a series of calculations are reported that probe the influence of the QM cluster size and the extended framework treatment in ONIOM calculations. This is done by comparing the differences in the structures and energetics obtained during simulations of cis-trans isomerisation of butene in H-ZSM-5 at varying level of accuracy. Seven different models have been employed; 3T, 5T and 10T DFT cluster models, and to more effectively encode the extended framework of ZSM-5; 3T:46T, 5T:46T, 10T:46T DFT:MM ONIOM models, and a 46T DFT cluster model. The results show that irrespective of the exact QM cluster size, relatively small gasphase clusters show clear limitations due to the neglect of the extended framework. In particular, the structural and electronic implications of using the different zeolite models have been rigorously assessed using the multivariate statistical method principal components analysis (PCA). © Springer Science+Business Media B.V. 2008.
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QM/MM and molecular dynamics investigation of the mechanism of covalent inhibition of TAK1 kinase
(2021-02-14)
Toviwek, Borvornwat
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Gleeson, Duangkamol
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Gleeson, M. Paul
TAK1 is a serine/threonine kinase which is involved in the moderation of cell survival and deathviathe TNFα signalling pathway. It is also implicated in a range of cancer and anti-inflammatory diseases. Drug discovery efforts on this target have focused on both traditional reversible ATP-binding site inhibitors and increasingly popular irreversible covalent binding inhibitors. Irreversible inhibitors can offer benefits in terms of potency, selectivity and PK/PD meaning they are increasingly pursued where the strategy exists. TAK1 kinase differs from the better-known kinase EGFR in that the reactive cysteine nucleophile targeted by electrophilic inhibitors is located towards the back of the ATP binding site, not at its mouth. While a wealth of structural and computational effort has been spent exploring EGFR, only limited studies on TAK1 have been reported. In this work we report the first QM/MM study on TAK1 aiming to better understand aspects of covalent adduct formation. Our goal is to identify the general base in the catalytic reaction, whether the process proceedsviaa stepwise or concerted pathway, and how the highly flexible G-loop and A-loop affect the catalytic cysteine located nearby.
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A theoretical investigation into the demethylation mechanism of dimethylsulfide over the W3O6 cluster
(2025-07-01)
Aziz, Hafiz Aji
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Kungwan, Nawee
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Gleeson, Duangkamol
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Saelee, Tinnakorn
;
Daengngern, Rathawat
Understanding how dimethyl sulfide (DMS) breaks down to form value-added products such as methanol on transition metal oxide catalysts is important for improving desulfurization processes. In this study, the reaction mechanism over a tungsten oxide cluster (W₃O₆) is elucidated using density functional theory (DFT) at the M06-L/LANL2DZ/aug-cc-pVTZ level of theory. Two competing mechanistic pathways were discovered over the W₃O₆ cluster: Pathway A) direct demethylation followed by methanol desorption and Pathway B) a water-assisted concerted demethylation pathway. Pathway A involves sequential steps with a moderate demethylation barrier (49.43 kcal/mol), but a significantly higher barrier (68.78 kcal/mol) for subsequent methanol formation, imposing a kinetic bottleneck. Remarkably, Pathway B, mediated by an explicit water molecule, facilitates a lower-barrier concerted transformation (56.19 kcal/mol), effectively bypassing the high-energy intermediate. Kinetic modeling via Transition State Theory and the Energetic Span Model reveal that despite the very low turnover frequency (TOF = 9.29 × 10−30 s⁻¹), the water-assisted pathway is energetically superior. These findings highlight the important role of water in helping the reaction proceed and offer insight for designing better catalysts for sulfur removal from DMS to methanol over the W₃O₆ cluster.
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Skin sensitization prediction using quantum chemical calculations: A theoretical model for the SNAr domain
(2014-01-21)
Promkatkaew, Malinee
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Gleeson, Duangkamol
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Hannongbua, Supa
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Gleeson, M. Paul
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 S<inf>N</inf>Ar 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.
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Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer
(2024-11-01)
Konsue, Adchata
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Lamtha, Thomanai
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Gleeson, Duangkamol
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Jones, Donald J.L.
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Britton, Robert G.
Epidermal growth factor receptor (EGFR) kinase has been implicated in the uncontrolled cell growth associated with non-small cell lung cancer (NSCLC). This has prompted the development of 3 generations of EGFR inhibitors over the last 2 decades due to the rapid development of drug resistance issues caused by clinical mutations, including T790M, L858R and the double mutant T790M & L858R. In this work we report the design, preparation and biological assessment of new irreversible 2,4-diaminopyrimidine-based inhibitors of EGFR kinase. Twenty new compounds have been prepared and evaluated which incorporate a range of electrophilic moieties. These include acrylamide, 2-chloroacetamide and (2E)-3-phenylprop-2-enamide, to allow reaction with residue Cys797. In addition, more polar groups have been incorporated to provide a better balance of physical properties than clinical candidate Rociletinib. Inhibitory activities against EGFR wildtype (WT) and EGFR T790M & L858R have been evaluated along with cytotoxicity against EGFR-overexpressing (A549, A431) and normal cell lines (HepG2). Selectivity against JAK3 kinase as well as physicochemical properties determination (logD<inf>7.4</inf> and phosphate buffer solubility) have been used to profile the compounds. We have identified 20, 21 and 23 as potent mutant EGFR inhibitors (≤20 nM), with comparable or better selectivity over WT EGFR, and lower activity at JAK3, than Osimertinib or Rociletinib. Compounds 21 displayed the best combination of EGFR mutant activity, JAK3 selectivity, cellular activity and physicochemical properties. Finally, kinetic studies on 21 were performed, confirming a covalent mechanism of action at EGFR.
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Computationally guided optimization of the antimalarial activity and physicochemical properties of 2,4-diaminopyrimidines
(2025-01-01)
Guntur, Guntur
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Gleeson, Duangkamol
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Anderson, Mark
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Mutter, Nicole
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Webster, Lauren
Plasmodium falciparum (Pf) is the most prevalent cause of malaria infections in humans. Due to the development of resistant strains, newer drugs, or drugs acting at novel targets are constantly being sought. Here, we report the design and preparation of 48 new 2,4-diaminopyrimidine derivatives targeting the Pf protein kinome. Bioinformatics methods have been used to identify the most probable target(s). Cheminformatics and molecular modelling have been used to guide the structural modifications. Our primary goal was to enhance the antimalarial activity of the series, reduce mammalian cytotoxicity, and increase aqueous solubility. The antimalarial activity of all 48 compounds has been assessed in chloroquine-resistant Pf3D7 strain and for their mammalian cytotoxicity in HepG2 cell lines. Phosphate buffer solubility, MDCK permeability, and metabolic clearance in human and rat microsomes were also assessed. Compounds 68 and 69 demonstrated good antimalarial activity (Pf IC<inf>50</inf>) of 0.05 and 0.06 μM, respectively, and good selectivity over the mammalian cell line (SI >100 fold). The compounds also demonstrated much improved aqueous solubilities of 989.7 and 1573 μg mL−1, respectively, along with moderate intrinsic clearance (∼3 mL min−1 g−1) and permeability (>60 nm s−1).
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QM methods in structure based design: Utility in probing protein-ligand interactions
(2010-12-01)
Gleeson, M. Paul
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Hannongbua, Supa
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Gleeson, Duangkamol
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.
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Synthesis and Characterization of Zeolite A from Industrial Fly Ash as a Green, Cost-Effective Cd2+ and Pb2+ Adsorbent for Wastewater Applications
(2025-02-18)
Sukchit, Darunee
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Prajuabsuk, Malee
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Lumlong, Saisamorn
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Inntam, Chan
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Punkvang, Auradee
According to the large amount of fly ash waste generated from the use of lignite coal as the primary fuel for electricity generation in the Mae Moh district of Lampang province, Thailand, efforts have been made in waste management to reduce and repurpose this industrial byproduct. In this study, lignite coal fly ash was used to synthesize zeolite A adsorbents for the treatment of wastewater contaminated with heavy metals. Characterization of the synthesized zeolite using XRD, XRF, BET, and SEM methods confirmed that it is zeolite A, with a calculated Si/Al molar ratio of approximately 1.19, closely matching the theoretical ratio of zeolite A. This zeolite A exhibited a high crystalline phase and a mesoporous structure, having a specific surface area of 37.10 m2/g and a total pore volume of 0.06 cm3/g. The performance of this zeolite A was evaluated for the adsorption of Cd2+ and Pb2+ in prepared solutions. The removal efficiencies of zeolite A for Cd2+ and Pb2+ were 99.65% ± 0.1% and 93.90% ± 0.5%, with maximum adsorption capacities of 17.3 ± 0.6 and 8.8 ± 0.1 mg/g, respectively. Additionally, zeolite A demonstrated reusability for the adsorption of Cd2+ and Pb2+, maintaining a removal efficiency of 80.52% ± 0.1% for Cd2+ over five reuse cycles, and 96.83% ± 0.7% for Pb2+ over one reuse cycle. The adsorption of Cd2+ and Pb2+ by zeolite A followed the Langmuir isotherm model and pseudo-second-order kinetic model. Moreover, the adsorption of Cd2+ and Pb2+ by zeolite A was found to be a spontaneous, endothermic process, as evidenced by increasingly negative Gibbs free energy change (ΔG°) values with rising temperature. Density functional theory (DFT) calculations were also performed to investigate the binding of Cd2+ and Pb2+ ions to zeolite A, providing insight into why Cd2+ exhibits a slightly higher affinity than Pb2+. The results showed that Cd2+ ions have a marginally greater affinity for zeolite A compared to Pb2+ (−85.72 vs −85.39 kcal/mol), which aligns with experimental findings. This study offers an alternative approach for reducing industrial waste by repurposing it for valuable applications, contributing to sustainable waste management practices that align with the principles of the bio-circular-green economy.
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QM/MM calculations in drug discovery: A useful method for studying binding phenomena?
(2009-03-23)
Gleeson, M. Paul
;
Gleeson, Duangkamol
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.

Gleeson, Duangkamol

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