title: Screening of Novel Inhibitors Against Leishmania donovani Calcium ion Channel to Fight Leishmaniasis.
abstract: Leishmania is an intracellular protozoan parasite which causes Leishmaniasis, a global health problem affecting millions of people throughout 89 different countries in the world. The current treatment which includes use of amphotericin B, antimonials, and others has major drawbacks due to toxicity, resistance, and extraordinary high cost. So there is an urgent need of development of new drug targets to fight against leishmaniasis. In this regard we have selected Leishmania donovani Ca2+ ion channel (Ld-CC) as potential drug target. Ld-CC regulates concentration of Ca2+ ions which is involved in several functions like flagellar motion, mitochondrial oxidative metabolism and entry inside the macrophages. Since Ld-CC has not been characterised yet, we performed homology modelling of Leishmania donovani Ca2+ ion channel (Ld-CC) and docking studies of ligand library against this channel. 542 compound library of National Cancer Institute (NCI) diversity 3 dataset selected for screening studies. The ligands ZINC17287336 and ZINC29590262 were selected as best energy conformers because they show highest binding affinity towards its target (Ld-CC). They interact with the active site residues in the pocket of Ld-CC which suggests that the docked conformations are good and acceptable. Moreover, these two selected compounds also have relatively high binding affinity than nifedipine and verapamil, known human calcium channel blockers which had been reported to have mild anti-leishmanial activity. Among these two top screened inhibitors the ligand ZINC29590262 shows poor binding affinity towards the Human voltagedependent L-type calcium channel subunit alpha-1C in comparison to the Ld-CC. Therefore, we proposed this ligand as the best inhibitor which shows 40% more binding affinity with Ld-CC than the human-VDCC. These results suggest that our screened ligand ZINC29590262 could act as novel drug and may show much better antileishmanial activity.
authors.affiliation: Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delhi, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kashif
authors.affiliation: 2Immunobiology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Partha P
authors.initials: PP
authors.lastname: Manna
authors.affiliation: Centre for Computational Biology & Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Shahpur, Kangra, Himachal Pradesh 176206, India.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Akhter
authors.affiliation: Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah. Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alaidarous
authors.affiliation: Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delh-110025i, India.
authors.forename: Abdur
authors.initials: A
authors.lastname: Rub
mesh_terms: D000981:Antiprotozoal Agents / Q000378:metabolism / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D015220:Calcium Channels / Q000378:metabolism*; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D012529:Saudi Arabia
chemical_list: D000981:Antiprotozoal Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels
keywords: Drug designing; Leishmania donovani
  Ca2+ ion channel; Leishmaniasis; homology modelling; virtual screening