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
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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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Computational Investigation of the Ru-Mediated Preparation of Benzothiazoles From N-Arylthioureas: Elucidation of the Reaction Mechanism and the Origin of Differing Substrate Reactivity
(2024-10-01)
Krawmanee, Pacharaporn
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Gleeson, M. Paul
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Gleeson, Duangkamol
Synthesis of novel benzothiazoles via intramolecular CS bond formation reactions is increasingly being explored since they have been found in a wide range of natural products and pharmaceutical agents. Sharma et al. reported the ruthenium-catalyzed preparation of novel benzothiazole derivatives from N-arylthiourea precursors, with a range of reaction yields and selectivity being observed. We have employed a density functional theory-based computational model to investigate the reaction mechanism leading to the benzothiazole product and help uncover the origin of the differing experimental yields and substrate specificities. We proposed a modified mechanistic scheme where the rate-determining step to be the synchronized breaking of the peroxide bond of the oxidizing agent with the concomitant proton-coupled electron transfer from the haloarene urea and a Ru-bound water molecule, not electrophilic RuC bond activation. Evidence for this being the rate-determining step is (a) the barrier is consistent with a lack of kinetic isotope effects associated with the ortho-H atom and (b) the computed rate-determining barriers for 10 N-arylthiourea substrates show good correlation with the observed yield.
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Role of alkali and alkaline-earth doped in zeolite A-derived from industrial waste toward direct ethanol dehydrogenation to acetaldehyde
(2026-06-08)
Sukchit, Darunee
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Prajuabsuk, Malee
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Inntam, Chan
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Lumlong, Saisamorn
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Pakamwong, Bongkochawan
In this study, a sustainable catalytic route for converting ethanol into value-added acetaldehyde was developed using alkali- and alkaline earth-modified zeolite A synthesized from sugarcane bagasse ash (SCBA). Zeolite A was first prepared via alkaline fusion followed by hydrothermal crystallization and subsequently doped with 1 wt% K^+ or Ca^2+ using incipient wetness impregnation. Comprehensive physicochemical characterization (X-ray fluorescence (XRF), X-ray diffraction (XRD), scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX), Fourier transform infrared spectroscopy (FTIR), nitrogen physisorption (N_2 physisorption), ammonia temperature-programmed desorption (NH_3-TPD), and carbon dioxide temperature-programmed desorption (CO_2-TPD)) confirmed the formation of a highly crystalline LTA framework with tunable acid-base properties upon cation incorporation. Catalytic evaluation demonstrated that ethanol dehydrogenation strongly depends on the balance of surface acid-base sites. The parent and Ca-modified zeolite A exhibited moderate acetaldehyde selectivity (11.2% and 21.2%, respectively), likely due to competing dehydration reactions. In contrast, K-modified zeolite A achieved higher acetaldehyde selectivity (51.8%) at 35.2% ethanol conversion, attributed to enhanced surface basicity and suppressed acidity. Mechanistic analysis suggests that K^+ and Ca^2+ promote ethanol dehydrogenation by facilitating ethoxide formation and β-hydrogen elimination on basic lattice oxygen sites. These findings demonstrate a cost-effective, noble-metal-free catalytic strategy and highlight the potential of SCBA-derived zeolite A as a sustainable platform for green ethanol upgrading.
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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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DFT Investigation of the catalytic conversion of acetic acid to acetone on the zeolite H-ZSM5
(2022-12-01)
Konsue, Adchatawut
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Gleeson, M. Paul
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Gleeson, Duangkamol
Biomaterials processing has become increasingly important in the chemical industry. Identification and optimization of processes to facilitate biomass conversion is therefore recognized as being of great importance. Carboxylic acids derived from biomaterials are important building blocks that can be used in a wide variety of industrial applications. As such, methods to process them in an efficient and cost-effective manner are highly desirable. In this study we report the use of theoretical methods to explore the catalytic conversion of acetic acid to acetone on the zeolite H-ZSM5. We have employed a 46T DFT cluster model to explore mechanistic proposals reported in the literature. We investigate the relative energetics associated with the formation of the proposed intermediates, including acyl-zeolite complexes, enols, acylium cations, ketenes, anhydrides, and beta-keto acids, that could potentially connect acetic acid to the desired product, acetone. This assessment would allow us to identify the most probable mechanism connecting the reactant to products. We predict a low energy pathway starting with the generation of a surface acyl, followed by an anhydride, with the rate determining step involving methyl group migration. The reaction is predicted to be bi-molecular and involves C-C bond formation, in line with proposals based on isotopic labelling experiments.
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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).

Gleeson, Duangkamol

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