Pharmacoinformatics based screening of combined synthetic and natural compounds to identify novel and in silico potential Bcl-2 inhibitors.

• Combined synthetic and natural compounds reported as Bcl-2 inhibitors were applied to generate pharmacophore and QSAR model. • ZINC database was screened to identify molecules with similar chemical features and predicted pIC50 from QSAR equation. • Docking, MD simulations with MM-PBSA calculations were performed to identify in silico potential Bcl-2 inhibitors. • Study identified ZINC07405677, ZINC41435991, ZINC71943283 and ZINC95430809 as potential hit molecules for cancer. The apoptotic balance of the cell is governed by Bcl-2 protein family. Increased expression of pro-survival members of Bcl-2 family is indicative of cell death evasion and cancer metastasis. The current therapeutic approach to regulate the Bcl-2 overexpression using small molecule, although effective, is limited by dose related toxicity. In the present study, a combination of features from synthetic drugs and phytochemicals are used to design drugs balances both safety and efficacy. In our approach, ligand-based pharmacophore model was generated using both the classes of drugs as input. Compounds with good fitness score and pharmacophore features were screened from ZINC database. The activity (pIC50) of the compounds were predicted on the basis of QSAR studies. From the analysis, four compounds ZINC07405677, ZINC41435991, ZINC71943283 and ZINC95430809 showed maximum activity with pIC50 of 17.6, 14.95,14.79 and 12.70 respectively. Given that pIC50 of 9.67 was the highest in literature reported compounds, it can be concluded that the ZINC compounds have demonstrated better Bcl-2 inhibition capacity in comparison. Further, docking, ADMET and molecular dynamics simulation studies against Bcl-2 helped in quantitatively assessing and confirming high activity, good stability and binding affinity of identified ZINC compounds. [ABSTRACT FROM AUTHOR]