Pharmacophore Design, Virtual Screening, Molecular Docking and Optimization Approaches to Discover Potent Thrombin Inhibitors.

Pharmacophore Design, Virtual Screening, Molecular Docking and Optimization Approaches to Discover Potent Thrombin Inhibitors. Comb Chem High Throughput Screen. 2013 May 22; Authors: Loganathan C, Sakkiah S, Lee KW, Kabilan S, Meganathan C Abstract Thrombin plays a central role in the regulation of haemostasis and thrombosis. Inhibition of thrombin is therefore an effective therapeutic target to prevent the formation of blood clots and related thromboembolic disorders. Hence, we have developed chemical feature based pharmacophore models of thrombin inhibitors. The best hypothesis, Hypo1, characterized with two hydrogen bond acceptors (A), one hydrophobic (H) and one ring aromatic (R) feature. Hypo1 was cross validated using various techniques to prove its robustness and statistical significance. The well validated model Hypo1 was used as 3D query to perform a virtual screening. The hits obtained from virtual screening were sorted by applying drug-like filters and molecular docking studies. Finally, 4 compounds were obtained as drug-like leads based on scoring functions, binding mode and molecular interactions at the active site. These 4 molecules were further optimized by adding different substitution at their side chains. When compared with the original database hits, optimized molecules were showed high scoring function, good binding mode and molecular interactions. Hence, we suggest that, upon optimization, these four database hits can act ...
Source: Combinatorial Chemistry and High Throughput Screening - Category: Chemistry Authors: Tags: Comb Chem High Throughput Screen Source Type: research