title: Homology modeling of LmxMPK4 of Leishmania mexicana and virtual screening of potent inhibitors against it.
abstract: Leishmaniasis is one of the most important diseases of mankind. In the life cycle of Leishmania mexicana, two most important developmental stages are observed. In insect vector it is in promastigote form and in mammalian macrophages is the amastigote form. The family of protein kinases are extremely important regulators of many different cellular processes such as transcriptional control, cell cycle development and differentiation, and also draw much attention as possible drug targets for protozaon parasites. Leishmania mexicana mitogen activated protein kinase 4 (LmxMPK4) is essential for proliferation and survival of the parasite promastigote and amastigote forms and is a potential drug target for leishmaniasis. The existing therapy for leishmaniasis is not enough due to host toxicity and drug resistance. The experimental 3D structure of this protein has not yet been determined. In this study, we have used homology modelling techniques to generate the 3D structure of LmxMPK4 and selected effective inhibitors by ZINC database on the basis of structure of berberine alkaloid for molecular docking studies with LmxMPK4. The inhibitors ZINC05999210, ZINC40402312 and ZINC40977377 were found to be more potent for inhibition of leishmaniasis due to the robust binding affinity and strong inhibition constant (Ki) of the protein-ligand interactions. This finding may help to understand the nature of MAP kinase and development of specific anti-leishmanial therapies.
authors.affiliation: Bioinformatics Centre, Indian Veterinary Research Institute, Izatnagar 243122, India. chhedilalgupta009@gmail.com
authors.forename: Chhedi Lal
authors.initials: CL
authors.lastname: Gupta
authors.forename: Mohd Kalim Ahmad
authors.initials: MK
authors.lastname: Khan
authors.forename: Mohd Faheem
authors.initials: MF
authors.lastname: Khan
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Tiwari
mesh_terms: D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D040681:Structural Homology, Protein; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000981:Antiprotozoal Agents; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases