Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 1; p. 115155
• Main Authors: Rana, Devika, Kalamuddin, Md, Sundriyal, Sandeep, Jaiswal, Varun, Sharma, Gaurav, Das Sarma, Koushik, Sijwali, Puran Singh, Mohmmed, Asif, Malhotra, Pawan, Mahindroo, Neeraj
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2020
• Subjects: Antimalarials; Antimalarials - chemistry; Antimalarials - pharmacology; Cysteine Endopeptidases - metabolism; Cysteine proteases; Docking; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Falcipain-2; Falcipain-3; Malaria; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Pharmacophore; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Structure-Activity Relationship; Cysteine proteases; Malaria; Falcipain-3; Falcipain-2; Antimalarials; Docking; Pharmacophore
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2019.115155

[Display omitted] Falcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures. Sixteen molecules were purchased and subject to in vitro enzyme (FP-2 and FP-3) inhibition assays. Two compounds showed in vitro inhibition of FP-2 and FP-3 at low µM concentration. The selectivity of the inhibitors can be explained based on the predicted interactions of the molecule in the active site. Further, the inhibitors were evaluated in a functional assay and were found to induce morphological changes in line with their mode of action arresting Plasmodium development. Compound 15 was most potent inhibitor identified in this study.