Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow

被引:32
作者
Musyoka, Thommas M. [1 ]
Kanzi, Aquillah M. [1 ,2 ]
Lobb, Kevin A. [1 ,3 ]
Bishop, Ozlem Tastan [1 ]
机构
[1] Rhodes Univ, Dept Biochem & Microbiol, Res Unit Bioinformat RUBi, POB 94, ZA-6140 Grahamstown, South Africa
[2] Univ Pretoria, FABI, Fac Nat & Agr Sci, Dept Genet, Pretoria, South Africa
[3] Rhodes Univ, Dept Chem, POB 94, ZA-6140 Grahamstown, South Africa
基金
美国国家卫生研究院;
关键词
malaria; homology modelling; docking; molecular dynamics; falcipains; ARTEMISININ RESISTANCE; BIOLOGICAL EVALUATION; FALCIPAIN INHIBITORS; HIGH-THROUGHPUT; PROTEIN; SEQUENCE; DERIVATIVES; DATABASE; DOCKING; COMPLEX;
D O I
10.1080/07391102.2015.1108231
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
Falcipain-2 (FP-2) and falcipain-3 (FP-3), haemoglobin-degrading enzymes in Plasmodium falciparum, are validated drug targets for the development of effective inhibitors against malaria. However, no commercial drug-targeting falcipains has been developed despite their central role in the life cycle of the parasites. In this work, in silico approaches are used to identify key structural elements that control the binding and selectivity of a diverse set of non-peptidic compounds onto FP-2, FP-3 and homologues from other Plasmodium species as well as human cathepsins. Hotspot residues and the underlying non-covalent interactions, important for the binding of ligands, are identified by interaction fingerprint analysis between the proteases and 2-cyanopyridine derivatives (best hits). It is observed that the size and chemical type of substituent groups within 2-cyanopyridine derivatives determine the strength of protein-ligand interactions. This research presents novel results that can further be exploited in the structure-based molecular-guided design of more potent antimalarial drugs.
引用
收藏
页码:2084 / 2101
页数:18
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