Design of metronidazole derivatives and flavonoids as potential non-nucleoside reverse transcriptase inhibitors using combined ligand- and structure-based approaches.

Acquired Immuno Defficiency Syndrome (AIDS) is one of the major global life threatening condition caused by Human Immunodeficiency Virus (HIV) and its prevalence has been increasing every year. Hence, this study has put its emphasis on HIV. Inhibition of Non-Nucleoside Reverse Transcriptase (NNRT) is considered as a well-developed target for HIV. Structure-based pharmacophore model was generated using the Phase tool of Schrodinger and screened database of metronidazole derivatives, flavonoids and metronidazole-flavonoid hybrid molecules. Compounds having good fitness score with similar pharmacophoric features as that of the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in market or clinical trials and metronidazole derivatives with reported anti-HIV activity are taken for molecular docking and rescoring by Glide and Prime tools. Hybrid molecules demonstrated good docking score and similar binding interactions as that of reference drugs. From Prime MM-GBSA rescoring, free binding energy was found less and protein-ligand complexes were stabilized with van der Waals free energy and nonpolar solvation terms. Further, atom-based QSAR model of reported metronidazole derivatives as NNRTIs was developed with good statistical values to further refine the database. Pharmacokinetic and toxicity prediction of the top compounds using some free wares like pkCSM and SwissADME reported that identified top compounds have good ADMET profile for oral administration, safe excretion and less toxicity. Study suggests that metronidazole-flavonoid hybrid molecules can be taken as lead molecule for further biological screening and has scope in future drug discovery as safe and potential NNRTIs.Communicated by Ramaswamy H. Sarma.