A pragmatic pharmacophore informatics strategy to discover new potent inhibitors against pim-3

Pim-3 (proviral integration site moloney murine leukemia virus-3) is an oncogene which encodes proteins belonging to serine/threonine kinase family and PIM subfamily. It is generally over-expressed in epithelial and hematological tumors. It is known to involve in numerous cellular functions such as cell growth, differentiation, survival, tumorigenesis, and apoptosis. It also plays a crucial role in regulation of signal transduction cascades. Therefore, it emerged as a hopeful therapeutic target for cancer treatment. In the current study, indole derivatives having potent inhibitory activity against Pim-3 were taken and pharmacophore-based virtual screening was carried out. A 5-point pharmacophore hypothesis with one hydrogen bond acceptor, one hydrogen bond donor, and three aromatic rings, i.e., ADRRR, was developed with acceptable R 2 and Q 2 values of 0.913 and 0.748, respectively. It was employed as a query and screening was conducted against Asinex and Otava lead library databases to screen out potent drug like candidates. The obtained compounds were subjected to SP, XP docking using 3D model of pim-3 which was constructed through comparative homology modelling, and finally binding free energies were calculated for top hits. The docking and binding free energy studies revealed that six hit molecules showed higher binding energy in comparison to the best active molecule. Finally, MD simulations of the top hit with the highest binding energy was carried out which indicated that the obtained hit N1 formed a stable complex with pim-3. We believe that these combined protocols will be helpful and cooperative to discover and design more potent pim-3 inhibitors in the near future.