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

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.

journal_name

Int J Mol Sci

journal_title

International journal of molecular sciences

authors

Amusengeri A,Astl L,Lobb K,Verkhivker GM,Tastan Bishop Ö

doi

10.3390/ijms20225574

subject

Has Abstract

pub_date

2019-11-08 00:00:00

issue

22

issn

1422-0067

pii

ijms20225574

journal_volume

20

pub_type

杂志文章

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