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

被引:17
作者
Amusengeri, Arnold [1 ]
Astl, Lindy [2 ]
Lobb, Kevin [1 ,3 ]
Verkhivker, Gennady M. [2 ,4 ,5 ]
Bishop, Ozlem Tastan [1 ]
机构
[1] Rhodes Univ, Dept Biochem & Microbiol, Res Unit Bioinformat RUBi, ZA-6140 Grahamstown, South Africa
[2] Chapman Univ, Schmid Coll Sci & Technol, Grad Program Computat & Data Sci, Orange, CA 92866 USA
[3] Rhodes Univ, Dept Chem, ZA-6140 Grahamstown, South Africa
[4] Chapman Univ, Sch Pharm, Dept Biomed & Pharmaceut Sci, Irvine, CA 92618 USA
[5] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, 9500 Gilman Dr, La Jolla, CA 92093 USA
基金
比尔及梅琳达.盖茨基金会; 新加坡国家研究基金会;
关键词
heat shock proteins; South African natural compounds; allosteric drugs; dynamic residue networks; betweenness centrality; HEAT-SHOCK-PROTEIN; MOLECULAR-MECHANICS; SUBSTRATE-BINDING; NETWORK ANALYSIS; CHAPERONE; REVEALS; IDENTIFICATION; INHIBITION; DYNAMICS; COMMUNICATION;
D O I
10.3390/ijms20225574
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:26
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