Biomedical subjects

Vudhichai Parasuk

Publications and source records attributed to Vudhichai Parasuk.

5 recordsLinked to original sources

PubMed2006

On the lower susceptibility of oseltamivir to influenza neuraminidase subtype N1 than those in N2 and N9.

Aiming to understand, at the molecular level, why oseltamivir (OTV) cannot be used for inhibition of human influenza neuraminidase subtype N1 as effectively as for subtypes N2 and N9, molecular dynamics simulations were carried out for the three complexes, OTV-N1, OTV-N2, and OTV-N9. The three-dimensional OTV-N2 and OTV-N9 initial structures were represented by the x-ray structures, whereas that of OTV-N1, whose x-ray structure is not yet solved, was built up using the aligned sequence of H5N1 isolated from humans in Thailand with the x-ray structure of the N2-substrate as the template. In comparison to the OTV-N2 and OTV-N9 complexes, dramatic changes were observed in the OTV conformation in the OTV-N1 complex in which two of its bulky side chains, N-acethyl (-NHAc) and 1-ethylproxy group (-OCHEt2), were rotated to adjust the size to fit into the N1 catalytic site. This change leads directly to the rearrangements of the OTV's environment, which are i), distances to its neighbors, W-178 and E-227, are shorter whereas those to residues R-224, E-276, and E-292 are longer; ii), hydrogen bonds to the two nearest neighbors, R-224 and E-276, are still conserved in distance and number as well as percentage occupation; iii), the calculated ligand/enzyme binding free energies of -7.20, -13.44, and -13.29 kcal/mol agree with their inhibitory activities in terms of the experimental IC50 of 36.1-53.2 nM, 1.9-2.7 nM, and 9.5-17.7 nM for the OTV-N1, OTV-N2, and OTV-N9 complexes, respectively; and iv), hydrogen-bond breaking and creation between the OTV and neighborhood residues are accordingly in agreement with the ligand solvation/desolvation taking place in the catalytic site.

Antiviral Agents↗

PubMed2006

Three-dimensional quantitative structure: activity relationship studies on diverse structural classes of HIV-1 integrase inhibitors using CoMFA and CoMSIA.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques, were applied to a set of 89 HIV-1 integrase (IN) inhibitors (training set=61, test set=28), belonging to 11 structurally different classes. The biological data for 3' processing mechanism were used. For CoMFA calculations, three different fitting methods for alignment process were investigated. The best CoMFA model yielded the cross-validated r(2) r(2)(cv) =0.698 and the non-cross-validated r(2) (r(2))=0.947. The derived model indicated the importance of steric (60.8%) as well as electrostatic (39.2%) contributions. For CoMSIA calculations, different combinations of the fields were tested. The best CoMSIA model gave r(2)(cv) =0.724 and r(2)=0.864. This model showed that steric (30.3%), hydrogen bond donor (43.4%) and hydrogen bond acceptor (26.3%) properties played major roles in HIV-1 IN inhibition. The mapping of hydrogen bond interaction fields with the HIV-1 IN active site gave details on hydrogen bond forming between ligands and enzyme. These obtained results agree well with the experimental observations that there should be hydrogen bond interactions between ligands and Glu152, Lys156 and Lys159 residues. The results not only lead to a better understanding of structural requirements of HIV-1 IN inhibitors but also can help in the design of new IN inhibitors.

HIV Integrase Inhibitors↗

PubMed2006

Effective discrimination of antimalarial potency of artemisinin compounds based on quantum chemical calculations of their reaction mechanism.

The reaction mechanism of 12 antimalarial artemisinin compounds with two competitive pathways was studied by means of quantum chemical calculations using the IMOMO(B3LYP/6-31(d,p):HF/3-21G) method. The oxygen-centered radicals, carbon-centered radicals, and transition states (TS) in both pathways were geometrically optimized. The obtained kinetic and thermodynamic energy profiles show that homolytic C-C cleavage reaction (pathway 2) is energetically more preferable than an intramolecular 1,5-hydrogen shift process (pathway 1), which is consistent with the docking calculations. However, compounds that can easily proceed along the pathway 1 have high activity. Therefore, both pathways are important for antimalarial activity. Moreover, effective discrimination between high and low activity compounds using EA1, deltaE1, and deltaE(1A-2A) was accomplished.

Animals↗

PubMed2004

Insights into saquinavir resistance in the G48V HIV-1 protease: quantum calculations and molecular dynamic simulations.

The spread of acquired immune deficiency syndrome has increasingly become a great concern owing largely to the failure of chemotherapies. The G48V is considered the key signature residue mutation of HIV-1 protease developing with saquinavir therapy. Molecular dynamics simulations of the wild-type and the G48V HIV-1 protease complexed with saquinavir were carried out to explore structure and interactions of the drug resistance. The molecular dynamics results combined with the quantum-based and molecular mechanics Poisson-Boltzmann surface area calculations indicated a monoprotonation took place on D25, one of the triad active site residues. The inhibitor binding of the triad residues and its interaction energy in the mutant were similar to those in the wild-type. The overall structure of both complexes is almost identical. However, the steric conflict of the substituted valine results in the conformational change of the P2 subsite and the disruption of hydrogen bonding between the -NH of the P2 subsite and the backbone -CO of the mutated residue. The magnitude of interaction energy changes was comparable to the experimental K(i) data. The designing for a new drug should consider a reduction of steric repulsion on P2 to enhance the activity toward this mutant strain.

Amino Acid Substitution↗

PubMedDate not supplied

Structure, dynamics and solvation of HIV-1 protease/saquinavir complex in aqueous solution and their contributions to drug resistance: molecular dynamic simulations.

As it is known that the understanding of the basic properties of the enzyme/inhibitor complex leads directly to enhancing the capability in drug designing and drug discovery. Molecular dynamics simulations have been performed to examine detailed information on the structure and dynamical properties of the HIV-1 PR complexed with saquinavir in the three protonated states, monoprotonates at Asp25 (Mono-25) and Asp25'(Mono-25') and diprotonate (Di-Pro) at both Asp25 and Asp25'. The obtained results support clinical data which reveal that Ile84 and Gly48 are two of the most frequent residues where mutation toward a protease inhibitor takes place. In contrast to the Ile84 mutation due to high displacement of Ile84 in the presence of saquinavir, source of the Gly48 mutation was observed to be due to the limited space in the HIV-1 PR pocket. The Gly48 was, on one side, found to form strong hydrogen bonds with saquinavir, while on the other side this residue was repelled by the hydrophobic Phe53 residue. In terms of inhibitor/enzyme binding, interactions between saquinavir and a catalytic triad of the HIV-1 PR were calculated using the ab initio method. The results show an order of the binding energy of Mono25<Di-pro<<Mono-25', suggesting that the active site in the HIV-1 PR complexed with saquinavir is monoprotonated states on Asp25. In contrast to the binding energy, 3, 6 and 12 hydrogen bonds between saquinavir and HIV-1 PR were found for the Mono-25, Mono-25' and Di-pro states, respectively. Discrepancy between the two trends suggests us to conclude that interaction between inhibitor and catalytic residues should be used as a criteria to enhance capability in drug designing and drug screening instead of using the total inhibitor/enzyme interaction which is normally reported in the literature. In addition, the distribution and binding of water molecules, in terms of hydrogen bonding, to the donor atoms of saquinavir were investigated and discussed, referring to that which was reported experimentally.

Catalysis↗