2,4-Dihydropyrano[2,3-c]pyrazole: Discovery of new lead as through pharmacophore modelling, atom-based 3D-QSAR, virtual screening and docking strategies for improved anti-HIV-1 chemotherapy

Due to the AIDS crisis, development of new, selective and safe non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains a high priority for medical research. The discovery of potential lead compounds by analogue based design studies was accomplished using 3D-QSAR and pharmacophore modelling of non-nucleoside reverse transcriptase inhibitors. A series of 24 diarylaniline analogues as NNRTIs were used to develop an atom based pharmacophore model. A five-point pharmacophore with two hydrogen bond acceptors (A), one donor (D) and two aromatic rings (R) as pharmacophore features was selected and exhibited a statistically significant correlation coefficient of R2 = 0.90 for the training set compounds and Q2 = 0.81 for a randomly chosen test set of compounds. The derived pharmacophore was used as a template to screen a specs database. The retrieved hits were progressively passed through filters, such as the predicted activity, fitness score, Lipinski screen and docking scores. The surviving 12 hits exhibited new scaffold (i.e., 2,4-dihydropyrano[2,3-c]pyrazole) for anti-HIV-1 chemotherapy as non-nucleoside reverse transcriptase inhibitors.