In silico three-dimensional pharmacophores for aiding the discovery of the Pfmrk (Plasmodium cyclin-dependent protein kinases) specific inhibitors for the therapeutic treatment of malaria

Abstract

The resurgence of malaria and lack of effective antimalarial drugs affect millions of people worldwide every year, causing several million deaths. With the emergence of structure-based drug design methodologies, a major thrust in drug discovery efforts has shifted towards targeting specific proteins in parasites that are involved in their metabolic pathways. Although cyclin-dependent kinases (CDKs), due to their direct role in cell cycle regulations, have been targeted for the development of cancer therapeutics, CDKs for Plasmodium falciparum have only been recently identified to be attractive for the discovery of antimalarials. One of the plasmodium CDK targets is Pfmrk. Being a putative homolog of Cdk7 and, thus, having the possibility of dual functions, both in cell cycle control and gene expression within the parasite, pfrmk has become an interesting antimalarial chemotherapeutic target. This review discusses how in silico methodologies, without the knowledge of the X-ray crystallographic structure of Pfmrk, particularly based on the development of pharmacophores on known inhibitors can aid the discovery and design of Pfmrk-specific inhibitors through virtual screening of compound databases and provides insights into the understanding of the mechanism of binding in the active site of this enzyme.

Keywords::

• compound database
• cyclin-dependent kinase
• in silico pharmacophore
• malaria
• plasmodial CDK (Pfmrk)
• virtual screening

Acknowledgements

Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting true views of the Department of the Army or the Department of Defense. Six figures, three tables and some portions of the text were reproduced with copyright permission from our earlier published article in the Journal of Medicinal Chemistry.