Structure-based Pharmacophore Clustering of Multi- Conformation Proteins: Application to Identify Novel and Diverse CypD Inhibitors

Objectives: Cyclophilin D (CypD) is a chief regulatory protein of the necroptosis pathway involved in various neurological disorders, and ablation/inhibition of this protein confers neuroprotection. Current in silico drug design strategies employ multiple structures of a protein target since they enable the identification of diverse inhibitor molecules. However, structure-based drug design against a protein target becomes challenging if it contains numerous known structures with varying ligand interactions. Considering all these structures for virtual screeing of database compounds would be inappropriate in view of the computational resources that might be demanded. Therefore, identifying appropriate structures with varied binding site conformations is of utmost importance in order to identify inhibitors with diverse scaffolds. Keywords: e-pharmacophore, ensemble pharmacophore, ensemble docking, dual ensemble screening, multiple conformation proteins, pharmacophore-based clustering, neurological disorders.