In Silico Elucidation and Inhibition Studies of Selected Phytoligands Against Mitogen-Activated Protein Kinases of Protozoan Parasites.
Parasitic MAPKs exhibiting significant divergence with humans and playing an imperative role in parasitic metabolic activities have been exploited from several years as important targets for development of novel therapeutics. In addition, the emergence of the drug-resistant variants of parasitic diseases in the recent years has aroused a great need for the development of potent inhibitors against them. In the present study, we selected the metabolically active MAPKs LmxMPK4, PfMAP2 and TbMAPK5 of the three parasitic protozoans Leishmania mexicana, Plasmodium falciparum and Trypanosoma brucei, respectively. The homology modeling technique was used to develop the 3D structures of these proteins, and the same was validated by PROCHECK, ERRAT, ProQ and ProSA web servers to check the reliability. Ten phytoligands were employed for molecular docking studies with these proteins to search for potent phytoligand as a broad spectrum inhibitor. In this regard, two phytoligands (aspidocarpine for LmxMPK4 and TbMAPK5 and cubebin for PfMAP2) were found to be more effective inhibitors, in terms of robust binding energy, strong inhibition constant and better interactions between protein-ligand complexes. Furthermore, predicted ADME and toxicity properties suggested that these identified phytoligands exhibited comparable results to control drugs potentiating them as persuasive therapeutic agents for Leishmania, Trypanosoma and Plasmodium sp.
Department of Biosciences, Integral University, Lucknow, 226026, India.
Chhedi Lal
CL
Gupta
Department of Bioengineering, Integral University, Lucknow, 226026, India.
Salman
S
Akhtar
Department of Bioinformatics, Indian Institute of Information Technology, Allahabad, 211012, India.
Nilesh
N
Kumar
Department of Biosciences, Integral University, Lucknow, 226026, India.
Jasarat
J
Ali
Department of Biosciences, Integral University, Lucknow, 226026, India.
Neelam
N
Pathak
Department of Biosciences, Integral University, Lucknow, 226026, India. preeti2874@gmail.com.
Preeti
P
Bajpai
D000595:Amino Acid Sequence; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010271:Parasites / Q000187:drug effects / Q000201:enzymology*; D010802:Phylogeny; D064209:Phytochemicals / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015203:Reproducibility of Results; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013816:Thermodynamics
D000977:Antiparasitic Agents; D008024:Ligands; D064209:Phytochemicals; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases
Mitogen-activated protein kinases; Molecular docking; Molecular modeling; Phylogenetic analysis; Phytoligands; Protozoan parasite