Gleeson, Duangkamol

Preferred name

Gleeson, Duangkamol

Main Affiliation

School of Science

duangkamol.gl@kmitl.ac.th

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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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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
;
Gleeson, M. Paul
;
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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Elucidation of the catalytic mechanism of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase using QM/MM calculations
(2018-01-01)
Jongkon, Nathjanan
;
Gleeson, Duangkamol
;
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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The skeletal isomerization in ferrierite: A theoretical assessment of the bi-molecular conversion of cis-butene to iso-butene
(2013-03-01)
Gleeson, Duangkamol
It is still not totally clear as to whether the skeletal isomerization of linear butenes to iso-butene in ferrierite occurs via a mono-molecular or bi-molecular process. To try and shed more light on this process, quantum chemical calculations were undertaken on both mechanisms. A large cluster model (H<inf>53</inf>O<inf>52</inf>Si<inf>35</inf>Al) has been employed here to study the bi-molecular process and these results are contrasted to the mono-molecular results previously reported by the author using the same model. The results suggest that a bi-molecular process can indeed result in the formation of iso-butene, as well as longer chained by-products as exemplified by 2,4,4-trimethylpent-2-ene. A rate determining step of 18.6 kcal/mol is found for the bi-molecular process, involving CC bond formation between the two monomers. The barrier is also predicted to be considerably lower than that of the mono-molecular reaction (24.5 kcal/mol). Nevertheless, given that 2,4,4-trimethylpent-2-ene has a considerably lower barrier to reaction, and is more energetically favourable, iso-butene product to might not be expected to form in large quantities via this route. © 2012 Elsevier B.V.
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Theoretical Evaluation of the Reaction Mechanism of Serine Hydroxymethyltransferase
(2019-01-17)
Santatiwongchai, Jirapat
;
Gleeson, Duangkamol
;
Gleeson, M. Paul
Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP)-dependent enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene THF. SHMT is a folate pathway enzyme and is therefore of considerable medical interest due to its role as an important intervention point for antimalarial, anticancer, and antibacterial treatments. Despite considerable experimental effort, the precise reaction mechanism of SHMT remains unclear. In this study, we explore the mechanism of SHMT to determine the roles of active site residues and the nature and the sequence of chemical steps. Molecular dynamics (MD) methods were employed to generate a suitable starting structure which then underwent analysis using hybrid quantum mechanical/molecular mechanical (QM/MM) simulations. The QM region consisted of 12 key residues, two substrates, and explicit solvent. Our results show that the catalytic reaction proceeds according to a retro-aldol synthetic process with His129 acting as the general base in the reaction. The rate-determining step involves the cleavage of the PLP-serine aldimine C <inf>α</inf> -C <inf>β</inf> bond and the formation of formaldehyde in line with experimental evidence. The pyridyl ring of the PLP-serine aldimine substrate exists in deprotonated form, being stabilized directly by Asp208 via a strong H-bond, as well as through interactions with Arg371, Lys237, and His211, and with the surrounding protein which was electrostatically embedded. This knowledge has the potential to impact the design and development of new inhibitors.
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Theoretical Investigation of the Enantioselective [4 + 2] Cycloaddition Reaction of o-Hydroxystyrene and Azlactone
(2019-04-05)
Jensupakarn, Napassorn
;
Gleeson, M. Paul
;
Gleeson, Duangkamol
;
Boonyarattanakalin, Kanokthip
Theoretical studies have been undertaken to rationalize the origin of the enantioselective Diels-Alder reaction (DA) of o-hydroxystyrene and azlactone catalyzed by (a) chiral BINOL-phosphoric acid (CPA) and (b) CPA and chiral guanidine (TBO). The sequence of events leading to increased enantioselectivity under the latter conditions have been studied using density functional theory (DFT) methods. The computational results indicate that both the mono- and co-catalytic processes proceed via stepwise [4 + 2] cycloaddition reactions involving three steps, which are (1) C-C bond formation, (2) C-O bond formation, and (3) the opening of the azlactone ring. This results in the formation of an oxygenous cycle with one chiral center. The origin of greater enantioselectivity under the latter catalytic conditions are discussed in terms of the structural characteristics and energetics of the intermediates and transition states formed on the potential energy surface of the competing reactions.
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Skin sensitization prediction using quantum chemical calculations: A theoretical model for the SNAr domain
(2014-01-21)
Promkatkaew, Malinee
;
Gleeson, Duangkamol
;
Hannongbua, Supa
;
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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Correction: Application of QM/MM and QM methods to investigate histone deacetylase 8
(2015-08-03)
Gleeson, Duangkamol
;
Gleeson, M. Paul
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QM methods in structure based design: Utility in probing protein-ligand interactions
(2010-12-01)
Gleeson, M. Paul
;
Hannongbua, Supa
;
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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Investigation on the interactions between glucomannans and bifidobacterium protein by using molecular dynamics simulations
(2018-01-01)
Jensupakarn, Napassorn
;
Chotpatiwetchkul, Warot
;
Gleeson, Duangkamol
;
Boonyarattanakalin, Kanokthip
Konjac glucomannan is a polysaccharide extracted from the Amorphophallus konjac K.Koch plant. It is often used as food additives due to their low toxicity, biodegradability and low calories. The unique properties of konjac glucomannan is its prebiotic activities. Konjac glucomannan which cannot be digested and absorbed in human stomachs and small intestines. Therefore, it is fermented in the large intestine and becomes food for the beneficial bacteria or probiotics especially bifidobacteria and lactobacilli in human colons. This study examined the effect of the size of konjac glucomannan on the prebiotic property. The interactions between the different degrees of polymerization of konjac glucomannan and Bifidobacterium protein were investigated in 0.15 M sodium chloride solution at 310 K by using molecular dynamics simulation. The results have shown that water molecules dramatically affect the alignment of konjac glucomannan in the system. The active site of Bifidobacterium protein that determined by the calculations are composed of ASP154, ARG49, ASN206, and ASN401. The lowest flexibility of GM5 structure shows strong interactions with Bifidobacterium protein. The most suitable size of konjac glucomannan that can bind with the protein has the degrees of polymerization no more than 8.

Gleeson, Duangkamol

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