caa a22 4500 445878924 CHVBK 20180317145536.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11030-010-9267-0 doi (NATIONALLICENCE)springer-10.1007/s11030-010-9267-0 CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements [Elektronische Daten] [Vanangamudi Murugesan, Nidhi Sethi, Yenamandra Prabhakar, Seturam Katti] 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. Springer Science+Business Media B.V., 2010 Comparative molecular field analysis (CoMFA) nationallicence Comparative molecular similarity indices analysis (CoMSIA) nationallicence Dipeptidyl peptidase IV inhibitors nationallicence Type 2 diabetes nationallicence Pyrrolidine analogues nationallicence DPP-IV nationallicence CoMFA : Comparative molecular field analysis nationallicence CoMSIA : Comparative molecular similarity indices analysis nationallicence GLP-1 : Glucagon-like peptide 1 nationallicence DPP : Dipeptidyl peptidase nationallicence PLS : Partial least-squares nationallicence Murugesan Vanangamudi Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut Sethi Nidhi Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut Prabhakar Yenamandra Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut Katti Seturam Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut Molecular Diversity Springer Netherlands 15/2(2011-05-01), 457-466 1381-1991 15:2<457 2011 15 11030 https://doi.org/10.1007/s11030-010-9267-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11030-010-9267-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Murugesan Vanangamudi Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut NATIONALLICENCE 700 1- Sethi Nidhi Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut NATIONALLICENCE 700 1- Prabhakar Yenamandra Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut NATIONALLICENCE 700 1- Katti Seturam Medicinal and Process Chemistry Division, Central Drug Research Institute, 226001, Lucknow, India aut NATIONALLICENCE 773 0- Molecular Diversity Springer Netherlands 15/2(2011-05-01), 457-466 1381-1991 15:2<457 2011 15 11030 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer