In silico 3-D structure prediction and molecular docking studies of inosine monophosphate dehydrogenase from Plasmodium falciparum
Institution:
1. Institute of Chemical Sciences, University of Peshawar, Peshawar-25120, Pakistan;2. State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, China;3. State Key Laboratory of Chemical Resource Engineering, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China;4. Beijing Key Lab of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Bei San Huan East Road, P.O. Box 53, Beijing 100029, China;1. School of Science, Jiangnan University, Wuxi, China;2. School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UK;1. SiSaf Ltd, Innovation Centre, Northern Ireland Science Park, Queen''s Island, Belfast, BT3 9DT, UK;2. Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy
Abstract:
Growing resistance in malarial parasites, particularly in Plasmodium falciparum needs a serious search for the discovery of novel drug targets. Inosine monophosphate dehydrogenase (IMPDH) is an important target for antimalarial drug discovery process in P. falciparum for the treatment of malaria. In the absence of x-ray crystal structure of this enzyme, homology modeling proved to be a reasonable alternate to study substrate binding mechanisms of this enzyme. In this study, a 3-D homology model for P. falciparum IMPDH was constructed taking human IMPDH (PDB code 1NF7) as template. Furthermore, an in-silico combinatorial library of ribavirin (RVP) derivatives (1347 molecules) was designed and virtually screened for ligands having selectively greater binding affinity with Plasmodium falciparum IMPDH relative to human IMPDH II. A total of five Ribavirin derivatives were identified as having greater binding affinity (−126 to −108 Kcal/mol and −9.4 to −8.6 Kcal/mol) with Plasmodium falciparum IMPDH. These five inhibitors should be used as selective and potent for Plasmodium falciparum IMPDH. Such type of study will provide information to synthetic medicinal chemist to enhance the potential of compounds (RVP derivatives) as chemotherapeutic agents to fight against the increasing burden of malarial infections.
