Computational Chemistry Unit Cell

Bangkok, Thailand

Computational Chemistry Unit Cell

Bangkok, Thailand
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Kaiyawet N.,Computational Chemistry Unit Cell | Lonsdale R.,University of Bristol | Lonsdale R.,Max-Planck-Institut für Kohlenforschung | Lonsdale R.,University of Marburg | And 3 more authors.
Journal of Chemical Theory and Computation | Year: 2015

Thymidylate synthase (TS) is a promising cancer target, due to its crucial function in thymine synthesis. It performs the reductive methylation of 2′-deoxyuridine-5′-phosphate (dUMP) to thymidine-5′-phosphate (dTMP), using N-5,10-methylene-5,6,7,8-tetrahydrofolate (mTHF) as a cofactor. After the formation of the dUMP/mTHF/TS noncovalent complex, and subsequent conformational activation, this complex has been proposed to react via nucleophilic attack (Michael addition) by Cys146, followed by methylene-bridge formation to generate the ternary covalent intermediate. Herein, QM/MM (B3LYP-D/6-31+G(d)-CHARMM27) methods are used to model the formation of the ternary covalent intermediate. A two-dimensional potential energy surface reveals that the methylene-bridged intermediate is formed via a concerted mechanism, as indicated by a single transition state on the minimum energy pathway and the absence of a stable enolate intermediate. A range of different QM methods (B3LYP, MP2 and SCS-MP2, and different basis sets) are tested for the calculation of the activation energy barrier for the formation of the methylene-bridged intermediate. We test convergence of the QM/MM results with respect to size of the QM region. Inclusion of Arg166, which interacts with the nucleophilic thiolate, in the QM region is important for reliable results; the MM model apparently does not reproduce energies for distortion of the guanidinium side chain correctly. The spin component scaled-Møller-Plessett perturbation theory (SCS-MP2) approach was shown to be in best agreement (within 1.1 kcal/mol) while the results obtained with MP2 and B3LYP also yielded acceptable values (deviating by less than 3 kcal/mol) compared with the barrier derived from experiment. Our results indicate that using a dispersion-corrected DFT method, or a QM method with an accurate treatment of electron correlation, increases the agreement between the calculated and experimental activation energy barriers, compared with the semiempirical AM1 method. These calculations provide important insight into the reaction mechanism of TS and may be useful in the design of new TS inhibitors. © 2015 American Chemical Society.

Kongsune P.,Computational Chemistry Unit Cell | Rungrotmongkol T.,Chulalongkorn University | Nunthaboot N.,Mahasarakham University | Yotmanee P.,Computational Chemistry Unit Cell | And 5 more authors.
Monatshefte fur Chemie | Year: 2012

The furin (FR) complex with each of four different sequences of hemagglutinin from the highly pathogenic H5N1 strains (HPH5), which were identified during the 2004-2010 influenza outbreaks in Thailand, were evaluated by molecular dynamics simulations, so as to compare the specificity and recognition of the enzyme-substrate binding. Relative to the conventional HPH5 inserted (H5Sq1, RERRRKKR), the S5-R or S6-R arginine residue is replaced by the smaller lysine in the H5Sq2 (RERKRKKR) and H5Sq3 (REKRRKKR) strains, respectively, whereas the S3-K lysine residue is deleted in H5Sq4 (RERRR-KR). The molecular dynamics results of the intermolecular interactions, in terms of hydrogen bonds and per-residue decomposition energy, between the substrate and furin revealed that the deletion of the positively charged amino acid at the S3 position in H5Sq4 leads to a notably weaker binding and specificity with the furin active site compared with that of FR-H5Sq1. A slight change in the substrate binding was found in the FR-H5Sq2 and FR-H5Sq3 complexes as a result of the replacement of the arginine with the shorter side-chained lysine (same positive charge). Altogether, the predicted binding free energy of the enzyme-substrate complexes was found to be in the following order: FR-H5Sq1 < FR-H5Sq2 ∼ FR-H5Sq3 << FR-H5Sq4. © Springer-Verlag 2011.

Rungrotmongkol T.,Computational Chemistry Unit Cell | Rungrotmongkol T.,Chulalongkorn University | Malaisree M.,Computational Chemistry Unit Cell | Nunthaboot N.,Mahasarakham University | And 2 more authors.
Amino Acids | Year: 2010

To predict the susceptibility of the probable 2009 influenza A (H1N1-2009) mutant strains to oseltamivir, MD/LIE approach was applied to oseltamivir complexed with the most frequent drug-resistant strains of neuraminidase subtypes N1 and N2: two mutations on the framework residues (N294S and H274Y) and the two others on the direct-binding residues (E119V and R292K) of oseltamivir. Relative to those of the wild type (WT), loss of drug-target interaction energies, especially in terms of electrostatic contributions and hydrogen bonds were dominantly established in the E119V and R292K mutated systems. The inhibitory potencies of oseltamivir towards the WT and mutants were predicted according to the ordering of binding-free energies: WT (-12.3 kcal mol-1) > N294S (-10.4 kcal mol-1) > H274Y(-9.8 kcal mol-1) > E119 V(-9.3 kcal mol-1) > R292K (-7.7 kcal mol-1), suggesting that the H1N1-2009 influenza with R292K substitution, perhaps, conferred a high level of oseltamivir resistance, while the other mutants revealed moderate resistance levels. This result calls for an urgent need to develop new potent anti-influenza agents against the next pandemic of potentially higher oseltamivir resistant H1N1-2009 influenza. © Springer-Verlag 2009.

Khuntawee W.,Computational Chemistry Unit Cell | Rungrotmongko T.,Chulalongkorn University | Hannongbua S.,Computational Chemistry Unit Cell | Hannongbua S.,Chulalongkorn University
Journal of Chemical Information and Modeling | Year: 2012

The cyclin dependent kinases (CDKs), each with their respective regulatory partner cyclin that are involved in the regulation of the cell cycle, apoptosis, and transcription, are potentially interesting targets for cancer therapy. The CDK6 complex with cyclin D (CDK6/cycD) drives cellular proliferation by phosphorylation of specific key target proteins. To understand the flavonoids that inhibit the CDK6/cycD functions, molecular dynamics simulations (MDSs) were performed on three inhibitors, fisetin (FST), apigenin (AGN), and chrysin (CHS), complexed with CDK6/cycD, including the two different binding orientations of CHS: FST-like (CHS-A) and deschloro-flavopiridol-like (CHS-B). For all three inhibitors, including both CHS orientations, the conserved interaction between the 4-keto group of the flavonoid and the backbone V101 nitrogen of CDK6 was strongly detected. The 3'-and 4'-OH groups on the flavonoid phenyl ring and the 3-OH group on the benzopyranone ring of inhibitor were found to significantly increase the binding and inhibitory efficiency. Besides the electrostatic interactions, especially through hydrogen bond formation, the van der Waals (vdW) interactions with the I19, V27, F98, H100, and L152 residues of CDK6 are also important factors in the binding efficiency of flavonoids against the CDK6/cycD complex. On the basis of the docking calculation and MM-PBSA method, the order of the predicted inhibitory affinities of these three inhibitors toward the CDK6/cycD was FST > AGN > CHS, which is in good agreement with the experimental data. In addition, CHS preferentially binds to the active CDK6 in a different orientation to FST and AGN but similar to its related analog, deschloroflavopiridol. The obtained results are useful as the basic information for the further design of potent anticancer drugs specifically targeting the CDK6 enzyme. © 2011 American Chemical Society.

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