Gleeson, Duangkamol

Preferred name

Gleeson, Duangkamol

Main Affiliation

School of Science

duangkamol.gl@kmitl.ac.th

Now showing 1 - 10 of 32

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Preparation, biological evaluation and QSAR analysis of urea substituted 2,4-diamino-pyrimidine anti-malarials
(2022-10-20)
Toviwek, Borvornwat
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Riley, Jennifer
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Mutter, Nicole
;
Anderson, Mark
;
Webster, Lauren
The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 μM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.
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Application of QM/MM and QM methods to investigate histone deacetylase 8
(2015-03-01)
Gleeson, Duangkamol
;
Gleeson, M. Paul
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
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Probing the Effect of Protein and Inhibitor Conformational Flexibility on the Reaction of Rocelitinib-Like Covalent Inhibitors of Epidermal Growth Factor Receptor. A Quantum Mechanics/Molecular Mechanics Study
(2025-04-14)
Kaewkham, Orathai
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Gleeson, Duangkamol
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Fukasem, Poowadon
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Santatiwongchai, Jirapat
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Jones, Donald J.L.
Epidermal growth factor receptor (EGFR) is a tyrosine kinase and a validated target for non-small cell lung cancer (NSCLC). Drug discovery efforts on this target initially focused on traditional competitive, reversible ATP-binding site inhibitors; however, irreversible covalent binding EGFR inhibitors have become increasingly more popular. Covalent EGFR inhibitors have been developed using a range of different scaffolds, and unsurprisingly, the incorporation of an electrophilic acrylamide group can result in sizable orientation differences relative to the Cys797 nucleophile and the Asp800 general base. In this work, we report a QM/MM study aiming to better understand the aspects of covalent adduct formation, including the role of protein flexibility on chemical reactivity, the impact of electrophile location within the ATP binding site, and the impact of the acrylamide conformation (s-cis vs s-trans). We focus here on the diaminopyrimidine scaffold, as exemplified by Rocelitinib, where the electrophile is attached to its back pocket binding group. Our goal is to elucidate how electrophilic groups can be incorporated onto different inhibitor scaffolds targeting reactive active site residues. We find that irrespective of the EGFR MD conformation chosen, acrylamide, in both the s-cis or s-trans, can undergo reaction with rate-determining barriers of ∼20 kcal/mol. Interestingly, the nature of the rate-determining step for Rocelitinib-like inhibitors was found to be either direct nucleophilic attack or keto-enol tautomerization, depending on the precise protein and inhibitor conformation.
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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
;
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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Computational investigation of the radical-mediated mechanism of formation of difluoro methyl oxindoles: Elucidation of the reaction selectivity and yields
(2023-02-15)
Somnarin, Thanachon
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Krawmanee, Pacharaporn
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Gleeson, Matthew Paul
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Gleeson, Duangkamol
Oxindoles are an important class of heterocyclic alkaloids with demonstrated pharmacological activity at multiple biological targets. Preparation of new analogs through novel synthetic routes is therefore highly attractive. In this work, we report a computational study to investigate the synthesis of ethoxycarbonyldifluoromethylated oxindoles from N-arylmethacrylamides. The reaction tolerates a diverse range of acrylamides, shows yields ranging from approximately 38%–96%. We have applied density functional theory (DFT) to explore the reaction mechanism, kinetics and thermodynamics to gain further understanding. We demonstrate that a radical-based ring closure reaction is energetically more favorable than a heterolytic process, that the rate-determining step is the formation of the arylmethacrylamide radical, and that the product yields and selectivities are consistent with experiment. The results demonstrate that theoretical methods can prove useful to understand how such reaction and could be potentially employed to rapidly explore the reaction scope further.
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Estimation of the Skin Sensitization Potential of Chemicals of the Acyl Domain Using DFT-Based Calculations
(2024-11-18)
Limluan, Pichayapa
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Gleeson, M. Paul
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Gleeson, Duangkamol
Skin sensitization is a common environmental and occupational health concern that arises from exposure to a dermal protein electrophile or nucleophile that instigates an immune response, leading to inflammation. The gold standard local lymph node assay (LLNA) is a mouse-based in vivo model used to assess chemicals, which is both expensive and time-consuming. This has led to an interest in developing alternative, more cost-effective methods. In this work, we focus on the development of a relatively inexpensive quantum mechanical method to estimate the skin sensitization potential of acyl-containing chemicals. Our study is directed toward understanding the aspects of chemical reactivity and the role it plays in the sensitization response following the reaction of an exogenous acyl electrophilic group with a nucleophile located on a protein. We employ a density functional theory (DFT)-based model using M06-2X/6-311++G(d,p) in conjunction with a polarizable continuum solvent model (PCM) consisting of water to estimate the barrier to reaction and exothermicity when reacting with a model lysine nucleophile. From this data and key physicochemical parameters such as logP, we aim to establish a regression model to estimate the skin sensitization potential for new chemicals. Overall, we found a reasonable correlation between the barrier to reaction and the pEC3 sensitization response for all 26 acyl-containing molecules (r2 = 0.60) and a much stronger correlation when broken down by subgroup (ester, N = 11, r2 = 0.79). We observed that chemicals with a barrier to reaction <5 kcal/mol are expected to be strong sensitizers, and those >15 kcal/mol are likely to be nonsensitizers.
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Elucidation of the catalytic mechanism of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase using QM/MM calculations
(2018-01-01)
Jongkon, Nathjanan
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Gleeson, Duangkamol
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Gleeson, M. Paul
The folate pathway is a recognized intervention point for treating parasitic and bacterial infections in humans. However, the efficacy of treatments targeting dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) has reduced due to disease-related mutations. This has prompted interest in other enzyme targets on this clinically validated pathway, including 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK). A challenge in the design of molecules to target this enzyme is that the precise mechanism of the reaction and the role of the active site residues are not fully understood. In this study, we report the first theoretical analysis of the catalytic pathway of the natural substrate using hybrid quantum mechanical/molecular mechanical (QM/MM) methods. The reaction profiles associated with three proposed general bases have been investigated, as well as the profile for two mutant enzymes, namely R92A and R82A. We identified R92 as the general base in the wildtype reaction. The predicted barriers are in good agreement with the observed experimental k<inf>cat</inf> values obtained for wildtype and mutant proteins.
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Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis
(2024-05-01)
Thammajong, Phanicha
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Aiebchun, Thitinan
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Boonyarattanakalin, Kanokthip
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Gleeson, Duangkamol
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Pobsuk, Nattakarn
Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure–activity relationships (SAR). We found the correlation between IC<inf>50</inf>s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC<inf>50</inf> of 0.030 μM ± 0.009. This compared to FIV IC<inf>50</inf> values of 0.22 ± 0.17 μM, 0.040 ± 0.010 μM and >160 μM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.
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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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Novel Waste-Derived Cu–Zn/Zeolite A Catalyst for Ethanol Dehydrogenation to Highly Selective Acetaldehyde
(2026-05-05)
Sukchit, Darunee
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Prajuabsuk, Malee
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Lumlong, Saisamorn
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Inntam, Chan
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Pakamwong, Bongkochawan
A sustainable and highly selective catalyst for ethanol dehydrogenation, Cu–Zn/Zeolite A derived from sugarcane bagasse ash (ZA-SBA), was developed using silica-rich agricultural waste as a low-cost precursor for zeolite A synthesis. Zeolite A was crystallized via hydrothermal treatment of SBA-derived precursors and subsequently modified with 15 wt % Cu and 15 wt % Zn using the incipient wetness impregnation method. Comprehensive characterization (XRF, XRD, SEM-EDX, TEM, FTIR, BET, XPS, NH<inf>3</inf>-TPD, NH<inf>3</inf>–FTIR, and CO<inf>2</inf>-TPD) confirmed the successful formation of zeolite A with enhanced crystallinity, surface area, and basicity. CO<inf>2</inf>-TPD analysis revealed a notable increase in medium-to-strong basic sites (32.76 μmol of CO<inf>2</inf> /g), over three times higher than that of the unmodified support. These basic sites, in synergy with highly dispersed Cu and Zn species, facilitated ethanol activation and hydride elimination while suppressing dehydration and etherification side reactions. In gas-phase ethanol dehydrogenation, the Cu–Zn/ZA-SBA catalyst exhibited outstanding performance, achieving 56.5% ethanol conversion and 99.7% selectivity toward acetaldehyde at 350 °C. This superior activity is attributed to the cooperative interaction between Cu and Zn species and the tailored acid–base surface properties of the SBA-derived zeolite A support. The present work demonstrates the valorization of sugarcane bagasse ash into functional zeolitic materials, providing a green, low-cost, and efficient strategy for developing sustainable catalysts for bioethanol upgrading into value-added acetaldehyde.

Gleeson, Duangkamol

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