title: Exploration of new drug-like inhibitors for serine/threonine protein phosphatase 5 of Plasmodium falciparum: a docking and simulation study.
abstract: Protein phosphorylation is an important mechanism that implicates in physiology of any organism including parasitic protozoa. Metallic protein Ser/Thr protein phosphatase 5 (PP5) controls various cellular signaling pathways of Plasmodium falciparum. The structure and inhibitory mechanism of PP5 in P. falciparum is not known. In fact, no experimental structural data are available for P. falciparum Ser/Thr protein phosphatase 5 (PfPP5) till date. Hence, we have proposed computer-generated model of catalytic subunit of PfPP5 and its inhibitory mechanism was analyzed. A set of 42 known natural inhibitors of protein phosphate family were docked against metal-binding catalytic site of PfPP5 and we found that cantharidin and its derivatives shows better binding energy among them. Similarity search was performed by taking these compounds as lead compounds against PubChem and ChemBank. The search result provides 3703 similar compounds; out of which 2245 qualified the Lipinski rule of five. Further, virtual screening of these compounds was performed and selected top 25 were selected on the basis of binding energy. In continuation, rigid and flexible docking of these screened compounds was performed to get the insight of interactions. Finally, top 5 compounds were verified for ADMET properties, and then, all are subjected to MD simulations for 25 ns in order to validate their stability. Compounds CBI: 3554182, CID: 23561913, and CID: 21168680 showed most stable binding, although some of hydrogen bonds pairing varied throughout simulation. These finding would be helpful to the medicinal chemists for the development of antimalarial drugs to combat this deadly disease.
authors.affiliation: a Department of Bioinformatics, Computer Centre-II , Indian Institute of Information Technology-Allahabad , Allahabad 211012 , India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.affiliation: b School of Biotechnology , Jawaharlal Nehru University , New Delhi 110067 , India.
authors.forename: Alka
authors.initials: A
authors.lastname: Jadaun
authors.affiliation: a Department of Bioinformatics, Computer Centre-II , Indian Institute of Information Technology-Allahabad , Allahabad 211012 , India.
authors.forename: Himansu
authors.initials: H
authors.lastname: Kumar
authors.affiliation: a Department of Bioinformatics, Computer Centre-II , Indian Institute of Information Technology-Allahabad , Allahabad 211012 , India.
authors.forename: Utkarsh
authors.initials: U
authors.lastname: Raj
authors.affiliation: a Department of Bioinformatics, Computer Centre-II , Indian Institute of Information Technology-Allahabad , Allahabad 211012 , India.
authors.forename: Pritish Kumar
authors.initials: PK
authors.lastname: Varadwaj
authors.affiliation: c Centre for Agricultural Bioinformatics , Indian Agricultural Statistics Research Institute , New Delhi 110012 , India.
authors.forename: A R
authors.initials: AR
authors.lastname: Rao
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding
chemical_list: D000962:Antimalarials; D008024:Ligands; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5
keywords: MD simulation; P. falciparum; PfPP5; cantharadin; rigid/flexible docking