Ligand-based 3D-QSAR analysis and virtual screening in exploration of new scaffolds as Plasmodium falciparum glutathione reductase inhibitors

Plasmodium falciparum glutathione reductases involved in redox homeostasis pathway of parasite are found to be the most emerging target in the treatment of malaria. In the present study, a 3D-QSAR pharmacophore model was developed, based on twenty-three 1,4-naphthoquinone derivatives reported previously with marked inhibition against glutathione reductase (GR). The pharmacophore model development and 3D-QSAR analysis was carried out by PHASE program. The hypothesis with best survival score was found to be AAHRR. Thus the resulting pharmacophore model contained two aromatic rings, a hydrophobic and two hydrogen-bond acceptor sites. A statistically reliable model with good predictive power (r2 = 0.8155, q2 = 0.7054, average rm2 = 0.745) was obtained. Using these pharmacophore features, we screened a library of 214,029 compounds (Asinex Database) to find potential ligands that could inhibit the PFGR protein. The compounds then subjected to a number of filters of virtual screening workflow of Schrödinger software. Here, we report the best seven compounds based on their docking scores and mode of interactions. The aromatic ring, hydrophobic group and hydrogen-bond acceptor effects contribute to the inhibitory activity. Binding interaction of the inhibitors can further provide the information regarding the role of different features in ligands responsible for linkage with receptor. Both compound 1 and screened hit with highest docking score (lead-1) found to interact with ASN 278, LYS 32, GLU 31, GLU 277, ASP 275, THR 38, LYS 151 within same binding pocket of PFGR enzyme. The backbone structural scaffolds of these seven lead compounds obtained after screening could serve as building blocks when designing drug-like molecules for inhibition of P. falciparum GR.