title: Novel hydrazine derivatives as selective DPP-IV inhibitors: findings from virtual screening and validation through molecular dynamics simulations.
abstract: The present study demonstrates and validates the discovery of two novel hydrazine derivatives as selective dipeptidyl peptidase-IV (DPP-IV) inhibitors. Virtual screening (VS) of publicly available databases was performed using virtual screening workflow (VSW) of Schrödinger software against DPP-IV and the most promising hits were selected. Selectivity was further assessed by docking the hits against homology modeled structures of DPP8 and DPP9. Two novel hydrazine derivatives were selected for further studies based on their selectivity threshold. To assess their correct binding modes and stability of their complexes with enzyme, molecular dynamic (MD) simulation studies were performed against the DPP-IV protein and the results revealed that they had a better binding affinity towards DPP-IV as compared to DPP 8 and DPP 9. The binding poses were further validated by docking these ligands with different softwares (Glide and Gold). The proposed binding modes of hydrazines were found to be similar to sitagliptine and alogliptine. Thus, the study reveals the potential of hydrazine derivatives as highly selective DPP-IV inhibitors.
authors.affiliation: Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Bioinformatics Infrastructure Facility (BIF), Jamia Hamdard, New Delhi, 110062, India.
authors.forename: Omprakash
authors.initials: O
authors.lastname: Tanwar
authors.forename: Girdhar Singh
authors.initials: GS
authors.lastname: Deora
authors.forename: Lalima
authors.initials: L
authors.lastname: Tanwar
authors.forename: Gautam
authors.initials: G
authors.lastname: Kumar
authors.forename: Sridhara
authors.initials: S
authors.lastname: Janardhan
authors.forename: Mumtaz
authors.initials: M
authors.lastname: Alam
authors.lastname: Shaquiquzzaman
authors.forename: Mymoona
authors.initials: M
authors.lastname: Akhter
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry*; D055808:Drug Discovery; D006834:Hydrazines / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D015203:Reproducibility of Results
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D006834:Hydrazines; C029424:hydrazine; D018819:Dipeptidyl Peptidase 4