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.
Method: In the present study, clustering of a large number of CypD structures was carried out by
comparing the pharmacophores derived from their binding sites. A representative structure from
each cluster was adopted to build an ensemble pharmacophore that was further employed in dual
ensemble screening of database compounds.
Results: Two compounds that exhibited better docking scores, compared to the already reported
CypD inhibitors, formed stable complexes and desirable interactions with the protein during molecular
dynamics (MD) simulation.