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Article

Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s

1
Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
2
Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA
3
Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa
4
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA
5
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(22), 5574; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225574
Received: 7 October 2019 / Revised: 24 October 2019 / Accepted: 27 October 2019 / Published: 8 November 2019
Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks. View Full-Text
Keywords: heat shock proteins; South African natural compounds; allosteric drugs; dynamic residue networks; betweenness centrality heat shock proteins; South African natural compounds; allosteric drugs; dynamic residue networks; betweenness centrality
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MDPI and ACS Style

Amusengeri, A.; Astl, L.; Lobb, K.; Verkhivker, G.M.; Tastan Bishop, Ö. Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s. Int. J. Mol. Sci. 2019, 20, 5574. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225574

AMA Style

Amusengeri A, Astl L, Lobb K, Verkhivker GM, Tastan Bishop Ö. Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s. International Journal of Molecular Sciences. 2019; 20(22):5574. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225574

Chicago/Turabian Style

Amusengeri, Arnold, Lindy Astl, Kevin Lobb, Gennady M. Verkhivker, and Özlem Tastan Bishop. 2019. "Establishing Computational Approaches Towards Identifying Malarial Allosteric Modulators: A Case Study of Plasmodium falciparum Hsp70s" International Journal of Molecular Sciences 20, no. 22: 5574. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225574

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