In silico screening for identification of pyrrolidine derivatives dipeptidyl peptidase-IV inhibitors using COMFA, CoMSIA, HQSAR and docking studies
- 7 Downloads
To explore the relationship between the structures of substituted pyrrolidine derivatives and their inhibition of dipeptidyl peptidase IV inhibitors. The QSAR, including CoMFA, CoMSIA and HQSAR, were applied to identify the key structures impacting their inhibitory potencies. The CoMFA, CoMSIA and HQSAR with cross-validated correlation coefficient (q2) value of 0.727, 0.870 and 0.939 and r2 value of 0.973, 0.981 and 0.949. Based on the structure–activity relationship revealed by the present study, we have designed a set of novel dipeptidyl peptidase IV inhibitors that showed excellent potencies in the developed models. Thus, our results allowed us to design new derivatives with desired activities.
KeywordsPyrrolidine CoMFA CoMSIA HQSAR Docking Dipeptidyl peptidase IV
The authors are thankful to Head, School of Pharmacy, DAVV Indore for providing necessary facilities. Shikha Jain thanks the All India Council for Technical Education (AICTE), New Delhi, India, for the financial support for this research.
- Deacon CF, Johnsen AH, Holst JJ (1995) Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Meta 80(3):952–957Google Scholar
- Defronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L (2008) Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloricin take: a randomized, cross-over study. Curr Med Res Opin 24:2943–2952CrossRefPubMedGoogle Scholar
- Fukushima H, Hiratate A, Takahashi M, Mikami A, Saito-Hori M, Munetomo E, Kitano K, Chonan S, Saito H, Suzuki A, Takaoka Y, Yamamoto K (2008) Synthesis and structure-activity relationships of potent 4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors. Bioorg Med Chem 16(7):4093–4106CrossRefPubMedGoogle Scholar
- SYBYL6.9, Tripos Inc., St. Louis, MO, USAGoogle Scholar
- Viswanadhan VN, Ghose AK, Revankar RG, Robins RK (1989) Atomic physicochemical parameters for three dimensional structure directed quantitative structure activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput Sci 29(3):163–172CrossRefGoogle Scholar
- Zhao X, Chen M, Huang B, Ji H, Yuan M (2011) Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies on a(1A)-adrenergic receptor antagonists based on pharmacophore molecular alignment. Int J Mol Sci 12:7022–7037CrossRefPubMedPubMedCentralGoogle Scholar