title: A Novel Peptide Thrombopoietin Mimetic Designing and Optimization Using Computational Approach.
abstract: Thrombopoietin receptor (TPOR) is a cytokine receptor protein present on the cell surface. The activation of TPOR by thrombopoietin (TPO) (a glycoprotein hormone) triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets. Recent studies on ex vivo megakaryocytopoiesis have evolved the possibilities of therapeutics uses. These findings have paved the way for the development of various TPO alternatives (recombinant TPO, peptide, and non-peptide TPO mimetics), which are useful in regenerative medicine. However, these alternatives possess various limitations such as induction of autoimmune effects, high production cost, low specificity, and hence activity. In the present study, a novel peptidic TPO mimetic was designed through computational studies by studying the binding sites of TPO and TMP to TPOR and analogs of known mimetics. Screening of combinatorial library was done through molecular docking using ClusPro. These studies indicated mimetic-9 as a significant molecule since it was found to have better binding score of -938.8 kcal/mol with seven hydrogen bonds and a high number of hydrophobic interactions, than known mimetic TMP with docking score of -798.4 kcal/mol and TMP dimer with docking score of -811.9 kcal/mol for TPOR. Mimetic9-TPOR complex was further assessed by the molecular dynamics simulation, and their complex was found to be stable with an RMSD value of 0.091 Å. While studying the parameters, mimetic-9 was found to have overall good physiochemical properties with positive grand average hydropathy (GRAVY) score and high instability index score and was found to be localized in the extracellular region. The designed mimetic-9 might prove to be a useful lead molecule for mimicking the role of TPO for in vitro platelet production with higher efficiency.
authors.affiliation: Founder and O/I Stem Cell Research Laboratory, Department of Biotechnology, INSPIRE Faculty, Delhi Technological University , Delhi , India.
authors.forename: Vimal Kishor
authors.initials: VK
authors.lastname: Singh
authors.affiliation: Department of Chemistry, University of Delhi , Delhi , India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, University of Delhi , Delhi , India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Kalsan
authors.affiliation: Stem Cell Research Laboratory, Department of Biotechnology, Delhi Technological University , Delhi , India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Saini
authors.affiliation: Department of Chemistry, University of Delhi , Delhi , India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
keywords: mimetic library designing; molecular docking; molecular dynamics simulation; thrombopoietin; thrombopoietin receptor