Gleeson, Duangkamol
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Item type:Publication, Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis(2024-05-01); ; Pobsuk, NattakarnFeline 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 (r<sup>2</sup> = 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. - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Theoretical Investigation of the Enantioselective [4 + 2] Cycloaddition Reaction of o-Hydroxystyrene and Azlactone(2019-04-05); 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. - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds(2022-12-15) - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Investigation on the interactions between glucomannans and bifidobacterium protein by using molecular dynamics simulations(2018-01-01); ; 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. - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Exploring the catalytic mechanism of dihydropteroate synthase: Elucidating the differences between the substrate and inhibitor(2017-01-01); ; ; Gleeson, M. PaulDihydropteroate synthase (DHPS) catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) with p-aminobenzoic acid (pABA) and is a well validated target for anti-malarial and anti-bacterial drugs. However, in recent years its utility as a therapeutic target has diminished considerably due to multiple mutations. As such, considerable structural biology and medicinal chemistry effort has been expended to understand and overcome this issue. To date no detailed computational analysis of the protein mechanism has been made despite the detailed crystal structures and multiple mechanistic proposals being made. In this study the mechanistic proposals for DHPS have been systematically investigated using a hybrid QM/MM method. We aimed to compare the energetics associated with S<inf>N</inf>1 and S<inf>N</inf>2 processes, whether the S<inf>N</inf>1 process involves a carbocation or neutral DHP intermediate, uncover the identity of the general base in the catalytic mechanism, and understand the differences in substrate vs. inhibitor reactivity. Our results suggest a reaction that follows an S<inf>N</inf>1 process with the rate determining step being C-O bond breaking to give a carbocation intermediate. Comparative studies on the inhibitor STZ confirm the experimental observations that it is also a DHPS substrate.