Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity
- Authors
- Rana, Devika; Kalamuddin, Md.; Sundriyal, Sandeep; Jaiswal, Varun; Sharma, Gaurav; Das Sarma, Koushik; Sijwali, Puran Singh; Mohmmed, Asif; Malhotra, Pawan; Mahindroo, Neeraj
- Issue Date
- Jan-2020
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Malaria; Cysteine proteases; Docking; Pharmacophore; Falcipain-2; Falcipain-3; Antimalarials
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY, v.28, no.1
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- Volume
- 28
- Number
- 1
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/78510
- DOI
- 10.1016/j.bmc.2019.115155
- ISSN
- 0968-0896
- Abstract
- 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 mu M 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.
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