Upon Plasmodium falciparum merozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub of intra-erythrocytic proliferative stages of parasite. Given its high abundance and multidimensional attributes in parasite life-cycle, this is a lucrative target for designing antimalarials. Towards this, we have virtually screened MyriaScreenII diversity collection of 10,000 drug-like molecules, which resulted in 18 compounds complementing ATP-binding pocket of CDPK1. In vitro screening for toxicity in mammalian cells revealed that these compounds are non-toxic in nature. Furthermore, SPR analysis demonstrated differential binding affinity of these compounds towards recombinantly purified CDPK1 protein. Selection of lead compound 1 was performed by evaluating their inhibitory effects on phosphorylation and ATP binding activities of CDPK1. Furthermore, in vitro biophysical evaluations by ITC and FS revealed that binding of compound 1 is driven by formation of energetically favorable non-covalent interactions, with different binding constants in presence and absence of Ca2+, and TSA authenticated stability of compound 1 bound CDPK1 complex. Finally, compound 1 strongly inhibited intra-erythrocytic growth of P. falciparum in vitro. Conceivably, we propose a novel CDPK1-selective inhibitor, step towards developing pan-CDPK kinase inhibitors, prerequisite for cross-stage anti-malarial protection.
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May 2020
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Cover Image
Cover Image
The cover image shows high resolution of the 20 lowest energy structures of kringle 2 of human plasminogen to AGL55-NS88.2 (top) and KT155-SS1448 (bottom). To learn more about this, see the article by Qiu and colleagues (pp. 1613–1630). The image was provided by Francis J. Castellino.
Research Article|
May 29 2020
Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like CDPK1, a multistage growth regulator of P. falciparum
Ravi Jain;
Ravi Jain
1Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Gautam Buddha Nagar, UP 201314, India
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Sakshi Gupta;
Sakshi Gupta
2School of Physical Sciences, Jawaharlal Nehru University, Delhi 110067, India
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Manoj Munde;
Manoj Munde
2School of Physical Sciences, Jawaharlal Nehru University, Delhi 110067, India
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Soumya Pati;
Soumya Pati
1Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Gautam Buddha Nagar, UP 201314, India
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Shailja Singh
1Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Gautam Buddha Nagar, UP 201314, India
3Special Center for Molecular Medicine, Jawaharlal Nehru University, Delhi 110067, India
Correspondence: Shailja Singh (shailja.jnu@gmail.com)
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Publisher: Portland Press Ltd
Received:
January 18 2020
Revision Received:
May 11 2020
Accepted:
May 13 2020
Accepted Manuscript online:
May 13 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (10): 1951–1970.
Article history
Received:
January 18 2020
Revision Received:
May 11 2020
Accepted:
May 13 2020
Accepted Manuscript online:
May 13 2020
Citation
Ravi Jain, Sakshi Gupta, Manoj Munde, Soumya Pati, Shailja Singh; Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like CDPK1, a multistage growth regulator of P. falciparum. Biochem J 29 May 2020; 477 (10): 1951–1970. doi: https://doi.org/10.1042/BCJ20200045
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