title: CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements.
abstract: The inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirements of the DPP-IV inhibitors is envisioned to identify the significant features toward design of selective inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour plots of pyrrolidine based analogues are used to analyze the structural requirements of a DPP-IV active site. The CoMFA model has shown a cross-validated q (2) of 0.651 with a non-cross-validated r (2) of 0.882 and explained 70.6% variance in the activity of external test compounds. In this, the steric and electrostatic fields have respectively contributed 59.8 and 40.2%, respectively, to the explained activity of the compounds. The CoMSIA model has shown optimum predictivity (cross-validated q (2) = 0.661; non-cross-validated r (2) = 0.803; external test set's predictive r (2) = 0.706) with four molecular fields namely, steric, electrostatic, hydrogen bond (HB)-donor, and HB-acceptor. The contour plots of molecular fields resulting from these studies have suggested: (i) steric restriction with small electron rich substituent at 2- and 3-position of pyrrolidine ring, (ii) presence of electropositive ring linker between the pyrrolidine head and aryl tail, (iii) presence of electron-rich groups around the aryl tail moiety, and (iv) presence of sulfonamide between the ring linker and aryl tail which would increase DPP-IV binding affinity of the compounds. These findings will help in the design of structurally related/new compounds as potential DPP-IV inhibitors.
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, 226001, India.
authors.forename: Vanangamudi
authors.initials: V
authors.lastname: Murugesan
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sethi
authors.forename: Yenamandra S
authors.initials: YS
authors.lastname: Prabhakar
authors.forename: Seturam B
authors.initials: SB
authors.lastname: Katti
mesh_terms: D020134:Catalytic Domain; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; C032519:pyrrolidine