Topomer CoMFA and Virtual Screening Studies of Azaindole Class Renin Inhibitors

Title:Topomer CoMFA and Virtual Screening Studies of Azaindole Class Renin Inhibitors

Volume: 17 Issue: 5

Author(s): Yuhong Xiang, Jia Song and Zhuoyong Zhang

Affiliation:

Keywords: Fragment-based drug design, renin inhibitors, surflex-dock, topomer CoMFA, topomer search, virtual screening.

Abstract: Direct renin inhibitors (DRIs) have increasingly shown a significant advantage in the treatment of hypertension and protection of target organs. In this paper, a series of azaindole class renin inhibitors were subjected to 3D-QSAR study using Topomer CoMFA. Five kinds of splitting mode for different fragment cutting and 6 different training and test sets grouping were attempted to build consensus models. The results indicated that 6 consensus models had similar predictability (q² and r² _pred) and stability (r²). The best model showed good stability and predictability (q² of 0.616, r² of 0.908). The r² _pred value of the external test set was 0.70, which means that the model had an excellent external predictive ability, and the robustness of the developed model was assessed by the Y-randomization test. This study also adopted the methodology of fragment-based drug design (FBDD) to virtual screen new renin inhibitors by using Topomer Search technology. The R₁-group of the compound No. 13 with the highest activity was chosen as the basic scaffold, and its remaining R₂-group acted as a query to screen 142,025 molecules of ZINC database for similar fragments. The obtained 30 fragments with the highest R₂-group contribution values were added to the basic scaffold respectively. Finally 30 new azaindole compounds with potent high activities were obtained. Further the binding modes were studied by using Surflex- Dock. The docking results showed good binding interactions of the designed compounds with the renin protein, thus the rationality of this design was further verified from the perspective of the renin receptor.

Cite this article as:

Xiang Yuhong, Song Jia and Zhang Zhuoyong, Topomer CoMFA and Virtual Screening Studies of Azaindole Class Renin Inhibitors, Combinatorial Chemistry & High Throughput Screening 2014; 17 (5) . https://dx.doi.org/10.2174/1386207317666140107094708