Relative assessment of different statistical instruments and measures for the prediction of promising outcomes using docking, virtual screening and ADMET analysis against HIV-RT

Reverse transcriptase is the most therapeutic target for the discovery of novel, potent, and non-toxic new anti-retroviral drugs. In the present work, various docking software such as Sybyl Surflex-Dock, OpenEye FRED, and Hermes GOLD were evaluated for their efficiency to reproduce known cognate inhibitors' conformations. Three metrics were used and compared to assess the performance of the applied scoring functions, i.e. enrichment factor, receiver operating characteristic (ROC) curves, and Bedroc analysis. Twelve different scoring functions of three softwares were used to assess their ability to rank the cognate ligand within the active site of its proteins. The extensive virtual screening task was performed on eight crystal structures, and the performance of docking and scoring was assessed by their ability to efficiently detect known active compounds enriched in the top-ranked of the list among a randomly selected dataset of the ten thousand compounds of the NCI database. The effectiveness of post-docking relaxation in Surflex was also evaluated. The top 20, 50, and 100 compounds were selected based on consensus scoring functions from all 48 proteins with different ligand complexes. Further, the shortlisted leads were subjected to ADMET via using Discovery Studio. The results further implicate the importance of various statistical tools that should be followed before large-scale virtual screening for the drug discovery process. In silico results demonstrating the experiment was successful. The study of the research covers the combinatorial in silico techniques such as benchmarking of the softwares and scoring functions, statistical tools applied for screening and different conformations of HIV-RT crystal structures for virtual screening with rigid and flexible molecular docking and molecular dynamics simulation approach. This study reveals a clear roadmap to identify novel scaffolds against HIV-RT for antiretroviral therapy, thus providing the remedial solutions of HIV related infections and other diseases caused by malfunctioning of the target protein. Communicated by Ramaswamy H. Sarma