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3D-QSAR studies of Dipeptidyl peptidase IV inhibitors using a docking based alignment

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Abstract

Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones and maintain glucose homeostasis; this makes it an attractive target for the development of drugs for diabetes. This paper reports 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique. The conformation of the molecules in the active site was obtained through docking methods. The QSAR models were generated on two training sets composed of 74 and 25 molecules which included phenylalanine, thiazolidine, and fluorinated pyrrolidine analogs. The 3D-QSAR models are robust with statistically significant r2, q2, and \({\text{r}}^{2}_{{{\text{pred}}}} \) values. The CoMFA and CoMSIA models were used to design some new inhibitors with several fold higher binding affinity.

The CoMFA contours around molecule D1T155 (a) steric contours - favored (green); disfavored (yellow) (b) electrostatic contours - electropositive (blue); electronegative (red)

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Acknowledgements

The computational facilities were jointly provided by the All India Council of Technical Education through grant (F. No. 8022/RID/NPROJ/RPS-5/2003-04) and the Department of Science and Technology through their FIST program (SR/FST/LSI-163/2003). R.R.S. Pissurlenkar thanks the Amrut Mody Research Foundation (AMRF) and M.S. Shaikh, the University Grants Commission (UGC) for financial support [Grant /F.No.7-16/2003(SR)].

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  1. Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India

    Raghuvir R. S. Pissurlenkar, Mushtaque S. Shaikh & Evans C. Coutinho

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  1. Raghuvir R. S. Pissurlenkar
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  2. Mushtaque S. Shaikh
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  3. Evans C. Coutinho
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Correspondence to Evans C. Coutinho.

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Pissurlenkar, R.R.S., Shaikh, M.S. & Coutinho, E.C. 3D-QSAR studies of Dipeptidyl peptidase IV inhibitors using a docking based alignment. J Mol Model 13, 1047–1071 (2007). https://doi.org/10.1007/s00894-007-0227-2

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  • DOI: https://doi.org/10.1007/s00894-007-0227-2

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