期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 34, 期 10, 页码 2084-2101出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2015.1108231
关键词
malaria; homology modelling; docking; molecular dynamics; falcipains
资金
- National Institutes of Health Common Fund [U41HG006941]
- Rhodes University Postgraduate Fund
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U41HG006941] Funding Source: NIH RePORTER
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.
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