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J Biomol Struct Dyn. 2016 Oct;34(10):2084-101. doi: 10.1080/07391102.2015.1108231. Epub 2016 Jan 28.

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

Author information

a Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology , Rhodes University , P.O. Box 94, Grahamstown 6140 , South Africa.
b Faculty of Natural and Agricultural Sciences, Department of Genetics, Forestry and Agricultural Biotechnology Institute (FABI) , University of Pretoria , Pretoria , South Africa.
c Department of Chemistry , Rhodes University , P.O. Box 94, Grahamstown 6140 , South Africa.


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.


docking; falcipains; homology modelling; malaria; molecular dynamics

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