Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated <i>in silico</i> approaches
Creators: name: Sharma, Shweta
name: Shubham Srivastava
name: Apeksha Shrivastava
name: Malik, Ruchi
name: Almalki, Faisal
name: Saifullah, Khalid
name: M. Mumtaz Alam
name: M. Shaqiquzzaman
name: Ali, Shakir
name: Mymoona Akhter
Publisher: name: Taylor & Francis
Year: 2019
Subjects: subject: Biophysics
subject: Biochemistry
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 80699 Information Systems not elsewhere classified
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: Computational Biology

description: The Dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these <i>in silico</i> techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure based screening against PDB ID: 5T4E. After Absorption, Distribution, Metabolism and Excretion (ADME) analysis of shortlisted compounds, consensus docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall<b>-20062</b>) was available which was procured through exchange program. Molecular Dynamic (MD) simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound <b>MolMall-20062</b> showed promising DPP-IV inhibition activity with IC<sub>50</sub>: 6.2µM. Compound <b>MolMall-20062</b> could be taken as a good lead for the development of DPP-IV inhibitors. <b>Abbreviations: ADME:</b> Absorption, Distribution, Metabolism and Excretion; <b>ChEBI:</b> Chemical Entities of Biological Interest; <b>DPP-IV:</b> Dipeptidyl peptidase IV; <b>DISCOtech:</b> Distance Comparisons<b>; HTVS:</b> High Throughput Virtual Screening; <b>MD:</b> Molecular Dynamics; <b>MM-GBSA:</b> Molecular Mechanics‐Generalized Born Surface Area; <b>OGTT:</b> Oral Glucose Tolerance Test; <b>PBVS:</b> Pharmacophore Based Virtual Screening; <b>PDB:</b> Protein Data Bank; <b>RMSD:</b> Root Mean Square Deviation; <b>ROC:</b> Receiver Operating Characteristics; <b>SP:</b> Standard Precision<b>; SBVS:</b> Structure Based Virtual Screening; <b>VS:</b> Virtual Screening; <b>XP:</b> Extra Precision.