Title:Pharmacophore Design, Virtual Screening, Molecular Docking and Optimization Approaches to Discover Potent Thrombin Inhibitors
Volume: 16
Issue: 9
Author(s): Chandrasekaran Loganathan, Sugunadevi Sakkiah, Keun Woo Lee, Senthamaraikannan Kabilan and Chandrasekaran Meganathan
Affiliation:
Keywords:
Common feature and ligand based pharmacophore, molecular docking, thrombin, thrombosis, virtual screening.
Abstract: Thrombin plays a key role in the regulation of hemostasis and thrombosis. Inhibition of thrombin is therefore
an effective therapeutic target to prevent the formation of blood clots and related thromboembolism disorders. Hence, we
have developed chemical feature based pharmacophore models of thrombin inhibitors. The best hypothesis, Hypo1, is
characterized with two hydrogen bond acceptors (A), one hydrophobic (H) and one ring aromatic (R) feature. Hypo1 was
cross validated using several techniques to prove its validity and statistical significance. The well validated model Hypo1
was used as a 3D query to perform virtual screening. The scores 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 modes and molecular interactions at the active site. These 4 molecules were further optimized by
adding different substitutions in their side chains. When compared to the original database hits, optimized molecules
showed high scoring function, good binding modes and molecular interactions. Hence, we suggest that, upon
optimization, these four database hits can act as potential virtual leads to design novel thrombin inhibitors. Also, our
model could be useful to retrieve the structurally diverse compounds from various databases.
