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

Authors

Arnold Amusengeri, Rhodes University
Lindy Astl, Chapman UniversityFollow
Kevin Lobb, Rhodes University
Gennady M. Verkhivker, Chapman UniversityFollow
Özlem Tastan Bishop, Rhodes University

Document Type

Article

Publication Date

11-8-2019

Abstract

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.

Comments

This article was originally published in International Journal of Molecular Sciences, volume 20, issue 22, in 2019. https://doi.org/10.3390/ijms20225574

Recommended Citation

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(22), 5574; https://doi.org/10.3390/ijms20225574

Peer Reviewed

1

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This work is licensed under a Creative Commons Attribution 4.0 License.