Computer-aided de novo ligand design and docking/molecular dynamics study of Vitamin D receptor agonists |
| |
Authors: | Xiu-Long Shen Midori Takimoto-Kamimura Jing Wei Qing-Zhi Gao |
| |
Institution: | (1) Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, People’s Republic of China;(2) Teijin Institute for Biomedical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191–8512, Japan; |
| |
Abstract: | 1α,25(OH)2D3, which is directly mediated by the vitamin D receptor (VDR), exerts a wide variety of biological actions. However, the treatment
with 1α,25(OH)2D3 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)2D3. 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)2D3) 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. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|