Binding mode prediction and identification of new lead compounds from natural products as renin and angiotensin converting enzyme inhibitors

Abstract

Virtual screening studies were performed with docking and pharmacophore methods on a natural products (NPs) data set to investigate its inhibitory effect on cardiovascular targets such as renin (REN) and angiotensin-converting enzymes (ACE). Conformers obtained from the ligand–protein complex (from pdb) and the flexialigned structure of the reference compounds were used to generate pharmacophore query models. The results derived from the analysis on natural product data set showed that the compounds such as Nat-4, Nat-59, Nat-99 and Nat-141 provided good results against REN and Nat-7, Nat-6, Nat-31, Nat-59 and Nat-61 are considered as good HITs against ACE. The present studies revealed that the compound Nat-59 has remarkable interaction with both the studied targets (ACE and REN). Also we have observed better effects for those compounds on the hERG target through the pharmacophore based virtual screening method, revealing that these can be used as antiarrythmic agents. A new lead compound (NLC-1) was designed on the basis of the pharmacophoric features of the selected HITs, provided good HIT properties by pharmacophore and docking studies. Molecular dynamics simulations were performed on the compound NLC-1 in order to find out the binding features of this molecule on the targets (ACE and REN). These results concluded that the natural compound identified from these studies and the designed compound (NLC-1) can have multiple activities on cardiovascular targets.