Qing-Sen Yu

3D-QSAR studies of HDACs inhibitors using pharmacophore-based alignment.

Histone deacetylases (HDACs) enzyme is a promising target for the development of anticancer drugs. The enzyme-bound conformation of Trichostatin A (TSA) (PDB ID:1C3R) as an inhibitor of HDACs was used to manually construct a pharmacophore model. This model was then successfully used to identify the bioactive conformation and align flexible and structurally diverse molecules. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on hydroxamate-based HDACs inhibitors based on phamacophore alignment. The best predictions were obtained with CoMFA standard model (q(2) = 0.726, r(2) = 0.998) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q(2) = 0.610, r(2) = 0.995). Both of the models were validated by an external test set, which gave a satisfactory predictive r(2) value of 0.800 and 0.732, respectively. Graphical interpretation of the results revealed important structural features of the inhibitors related to the active site of HDACs. The results may be exploited for further design and virtual screening for some novel HDACs inhibitors.

Quantitative structure-chromatographic retention relationship for polycyclic aromatic sulfur heterocycles.

Polycyclic aromatic sulfur heterocycles (PASHs) are of concern in petroleum geochemistry and environmental chemistry. In the present study, geometrical optimization and electrostatic potential calculations have been performed for 114 PASHs reported previously at the HF/6-31G* level of theory. A group of 25 statistically based parameters have been extracted. Linear relationships between gas-chromatographic retention index (RI) and the structural descriptors have been established by stepwise linear regression analysis. The result shows that two quantities derived from positive electrostatic potential on molecular surface, V(s)(+) (the average value of the positive electrostatic potentials on molecular surface) and sigma(+)(2) (a measure of dispersion tendency of positive electrostatic potential), together with V(mc) (the molecular volume) and E(HOMO) (the energy of the highest occupied molecular orbital) can be well used to express the quantitative structure-retention relationship (QSRR) of PASHs. Predictive capability of the model has been demonstrated by leave-one-out cross-validation with the cross-validated correlation coefficient (R(CV)) of 0.992. Furthermore, when splitting the 114 PASH samples into calibration and test sets in the ratio of 2:1, a similar treatment yields an equation of almost equal statistical quality and very similar regression coefficients, validating the robustness of our model. Predictions for six PASHs from other source have also been made. The QSRR model established may provide a new powerful method for predicting chromatographic properties of aromatic organosulfur compounds.

Insight into the activity of SARS main protease: Molecular dynamics study of dimeric and monomeric form of enzyme

The phenomenon that SARS coronavirus main protease (SARS Mpro) dimer is the main functional form has been confirmed by experiment. However, because of the absence of structural information of the monomer, the reasons for this remain unknown. To investigate it, two molecular dynamics (MD) simulations in water for dimer and monomer models have been carried out, using the crystal structure of protomer A of the dimer as the starting structure for the monomer. During the MD simulation of dimer, three interest phenomena of protomer A have been observed: (i) the distance between NE2 of His41 and SG of Cys145 averages 3.72 Å, which agrees well with the experimental observations made by X‐ray crystallography; (ii) His163 and Glu166 form the “tooth” conformational properties, resulting in the specificity for glutamine at substrate P1 site; and (iii) the substrate‐binding pocket formed by loop 140–146 and loop 184–197 is large enough to accommodate the substrate analog. However, during the MD simulation of the monomer complex, the three structural characteristics are all absent, which results directly in the inactivation of the monomer. Throughout the MD simulation of the dimer, the N‐terminus of protomer B forms stable hydrogen bonds with Phe140 and Glu166, through which His163, Glu166, and loop 140–146 are kept active form. Furthermore, a water‐bridge has been found between the N‐terminus of protomer B and Gly170, which stabilizes His172 and avoids it moving toward Tyr161 to disrupt the H‐bond between Tyr161 and His163, stabilizing the conformation of His163. The interactions between the N‐terminus and another monomer maintain the activity of dimer. Proteins 2007.

Structural basis for the complete loss of GSK3β catalytic activity due to R96 mutation investigated by molecular dynamics study

Many Ser/Thr protein kinases, to be fully activated, are obligated to introduce a phospho‐Ser/Thr in their activation loop. Presently, the similarity of activation loop between two crystal complexes, i.e. glycogen synthase kinase 3β (GSK3β)‐AMPNP and GSK3β‐sulfate ion complex, indicates that the activation segment of GSK3β is preformed requiring neither a phosphorylation event nor conformational changes. GSK3β, when participated in glycogen synthesis and Wnt signaling pathways, possesses a unique feature with the preference of such substrate with a priming phosphate. Experimental mutagenesis proved that the residue arginine at amino acid 96 mutations to lysine (R96K) or alanine (R96A) selectively abolish activity on the substrates involved in glycogen synthesis signaling pathway. Based on two solved crystal structures, wild type (WT) and two mutants (R96K and R96A) GSK3β‐ATP‐phospho‐Serine (pSer) complexes were modeled. Molecular dynamics simulations and energy analysis were employed to investigate the effect of pSer involvement on the GSK3β structure in WT, and the mechanisms of GSK3β deactivation due to R96K and R96A mutations. The results indicate that the introduction of pSer to WT GSK3β generates a slight lobe closure on GSK3β without any remarkable changes, which may illuminate the experimental conclusion, whereas the conformations of GSK3β and ATP undergo significant changes in two mutants. As to GSK3β, the affected positions distribute over activation loop, α‐helix, and glycine‐rich loop. Based on coupling among the mentioned positions, the allosteric mechanisms for distorted ATP were proposed. Energy decomposition on the residues of activation loop identified the important residues Arg96 and Arg180 in anchoring the phosphate group. Proteins 2009.