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

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

  • Bioorg Med Chem. 2020 Jan 1;28(1):115155. doi: 10.1016/j.bmc.2019.115155.
Devika Rana 1,  Md Kalamuddin 2,  Sandeep Sundriyal 3,  Varun Jaiswal 1,  Gaurav Sharma 1,  Koushik Das Sarma 1,  Puran Singh Sijwali 4,  Asif Mohmmed 2,  Pawan Malhotra 5,  Neeraj Mahindroo 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229, India.
  • 2 International Centre for Genetic Engineering and Biotechnology, Aruna Asif Ali Marg, New Delhi 110067, India.
  • 3 Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
  • 4 CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, Telangana, India.
  • 5 International Centre for Genetic Engineering and Biotechnology, Aruna Asif Ali Marg, New Delhi 110067, India. Electronic address: pawanm@icgeb.res.in.
  • 6 School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229, India; School of Health Sciences, University of Petroleum and Energy Studies, Energy Acres, Bidholi, Via Premnagar, Uttrakhand 248007, India. Electronic address: Neeraj.Mahindroo@yahoo.com.
PMID: 31744777 DOI: 10.1016/j.bmc.2019.115155
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 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.

Keywords

Antimalarials; Cysteine proteases; Docking; Falcipain-2; Falcipain-3; Malaria; Pharmacophore.

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