{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T14:16:45Z","timestamp":1776694605600,"version":"3.51.2"},"reference-count":79,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR40151\/BTIS\/137\/5\/2021"],"award-info":[{"award-number":["BT\/PR40151\/BTIS\/137\/5\/2021"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.<\/jats:p>","DOI":"10.3390\/molecules26092742","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T10:06:12Z","timestamp":1620381972000},"page":"2742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP"],"prefix":"10.3390","volume":"26","author":[{"given":"Sadaf","family":"Shehzad","sequence":"first","affiliation":[{"name":"Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajan","family":"Pandey","sequence":"additional","affiliation":[{"name":"Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawan","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7548-8835","authenticated-orcid":false,"given":"Dinesh","family":"Gupta","sequence":"additional","affiliation":[{"name":"Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/cbic.200400313","article-title":"Molecular Machines for Protein Degradation","volume":"6","author":"Groll","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1126\/science.286.5446.1888","article-title":"Posttranslational Quality Control: Folding, Refolding, and Degrading Proteins","volume":"286","author":"Wickner","year":"1999","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1101\/gad.11.7.815","article-title":"Protein quality control: Triage by chaperones and proteases","volume":"11","author":"Gottesman","year":"1997","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1128\/jb.172.4.1791-1797.1990","article-title":"The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase","volume":"172","author":"Lipinska","year":"1990","journal-title":"J. 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