Computer-aided de novo ligand design and docking/molecular dynamics study of vitamin D receptor agonists.

1α,25(OH)(2)D(3), which is directly mediated by the vitamin D receptor (VDR), exerts a wide variety of biological actions. However, the treatment with 1α,25(OH)(2)D(3) is limited because of its side effects. Many analogs and several nonsteroidal mimics with potent biological activity have been reported so far, and our rationale for designing the VDR agonists was on the basis of computer-aided drug design method by de novo design of A-ring and C/D-ring position of 1α,25(OH)(2)D(3). Pyrimidine-2,4-diamine was selected as A-ring, and naphthalene and benzene were chosen as C/D-ring. By linking different components, a virtue compound library was obtained. To evaluate the contribution to activity of each component, we performed a series of automated molecular docking operations. Results revealed that the 19-dimethyl derivatives (the C-19 position correspond to C-20 in 1α,25(OH)(2)D(3)) show the favorable docking affinity to VDR. Moreover, the docking results are quite robust when further validated by molecular dynamics simulations. In addition, by free energy analysis using molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, the driving force of the binding between VDR and the ligands is proved to be hydrophobic interactions. Thus, a possible strategy to design new series of VDR agonists is proposed. The strategy can be successfully applied to explain the high potential activities of the 19-dimethyl derivatives. It is anticipated that the findings reported here may provide useful information for designing effective VDR agonists as well as the therapeutic treatment of VDR-related diseases.

Docking and molecular dynamics study on the inhibitory activity of novel inhibitors on epidermal growth factor receptor (EGFR).

EGFR is the cell-surface receptor. Its overexpression or overactivity has been associated with a number of cancers, including breast, lung, ovarian, and anal cancers. Many therapeutic approaches are aimed at the EGFR. A series of 2, 7-diamino-thiazolo [4,5-d] pyrimidine analogues are among the most highly potent and selective inhibitors of EGFR described to date. For in-depth investigation into the structural and chemical features responsible for the binding recognition mechanism concerned, as well as for exploring the binding pocket of these compounds, we performed a series of automated molecular docking operations. It was revealed that the binding site consisted of three main areas (P1, P2 and P3) composed of most of the hydrophobic amino acids able to accommodate the lipophilic arms of the compounds investigated. However, the solvent interface did not make much contribution to the binding of the inhibitors. The presence of residues Met793 and Asp855 may also be responsible for the binding recognition through H-bond interactions, with Phe856 through a T-shape π-π stacking interaction. The interaction model and pharmacophore of EGFR inhibitors were derived that can be successfully used to explain the different biologic activities of these inhibitors. Moreover, the docking results were quite robust as further validated by molecular dynamics. It is anticipated that the findings reported here may provide very useful information or clue for designing effective drugs for the therapeutic treatment of EGFR-related cancer.

3D-QSAR studies of boron-containing dipeptides as proteasome inhibitors with CoMFA and CoMSIA methods.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of dipeptide boronate proteasome inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 46 molecules served to establish the models. The optimum CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q(2)) of 0.676 and 0.630 and conventional coefficients (r(2)) of 0.989 and 0.956, respectively. The predictive capacities of both models were successfully validated by calculating a test set of 13 molecules that were not included in the training set. The predicted correlation coefficients (r(2)(pred)) of CoMFA and CoMSIA are 0.963 and 0.919, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of beta5 subunit of 20S proteasome, which suggests that the 3D-QSAR models constructed in this paper can be used to guide the development of novel dipeptide boronate inhibitors of 20S proteasome.

[Advances in the study of A2B adenosine receptor antagonists].

A2B adenosine receptor is involved in the control of mast cell degranulation, interleukin-8 synthesis and cell growth. A2B adenosine receptor antagonists may serve as novel drugs for asthma, Alzheimer' s disease, cystic fibrosis and type-II diabetes. Therefore, seeking for the highly selective A2B adenosine receptor antagonists has been one of great interest. The molecular basis, structure-activity relationship of selective A2B adenosine receptor antagonists and their interactions with A2B adenosine receptor were reviewed.