Abstract
Dipeptidyl peptidase IV (DPP-IV) is an attractive target, and its launched inhibitors have made great significance to clinical therapy of type 2 diabetes. For developing high potent DPP-IV inhibitors, ligand- and structure-based approaches were applied for the optimization of cyanopyrrolidine in this study. Two statistically significant 3D-QSAR models (CoMFA with q2, 0.585; r2, 0.963; CoMSIA with q2, 0.678; r2, 0.949) were developed. In combination with the structure-based pharmacophore model, fundamental structural requirements and pharmacophoric features for R groups were determined. Suitable fragments for different R groups were retrieved for the generation of novel molecules. After being evaluated by molecular docking, QuaSAR descriptors filter and 3D-QSAR activity prediction, active DPP-IV inhibitors were found. The reliability indicated this workflow can be applied to facilitate lead optimization for DPP-IV and even for other drug targets.
Keywords: DPP-IV, 3D-QSAR, pharmacophore, fragment, type 2 diabetes.
Letters in Drug Design & Discovery
Title:De Novo Design of High Potent DPP-IV Inhibitors Based on the Scaffold of Cyanopyrrolidine
Volume: 12 Issue: 6
Author(s): Yu-Lei Jiang, Hao-Liang Yuan, Wei-Wei Zhang, Hai-Chun Liu, Yan-Min Zhang, Xiao Xiong, Jin-Xing Xu, Shuai Lu, Tao Lu and Ya-Dong Chen
Affiliation:
Keywords: DPP-IV, 3D-QSAR, pharmacophore, fragment, type 2 diabetes.
Abstract: Dipeptidyl peptidase IV (DPP-IV) is an attractive target, and its launched inhibitors have made great significance to clinical therapy of type 2 diabetes. For developing high potent DPP-IV inhibitors, ligand- and structure-based approaches were applied for the optimization of cyanopyrrolidine in this study. Two statistically significant 3D-QSAR models (CoMFA with q2, 0.585; r2, 0.963; CoMSIA with q2, 0.678; r2, 0.949) were developed. In combination with the structure-based pharmacophore model, fundamental structural requirements and pharmacophoric features for R groups were determined. Suitable fragments for different R groups were retrieved for the generation of novel molecules. After being evaluated by molecular docking, QuaSAR descriptors filter and 3D-QSAR activity prediction, active DPP-IV inhibitors were found. The reliability indicated this workflow can be applied to facilitate lead optimization for DPP-IV and even for other drug targets.
Export Options
About this article
Cite this article as:
Jiang Yu-Lei, Yuan Hao-Liang, Zhang Wei-Wei, Liu Hai-Chun, Zhang Yan-Min, Xiong Xiao, Xu Jin-Xing, Lu Shuai, Lu Tao and Chen Ya-Dong, De Novo Design of High Potent DPP-IV Inhibitors Based on the Scaffold of Cyanopyrrolidine, Letters in Drug Design & Discovery 2015; 12 (6) . https://dx.doi.org/10.2174/1570180812666141201223016
DOI https://dx.doi.org/10.2174/1570180812666141201223016 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Novel Role of NPC1L1 in the Regulation of Hepatic Metabolism: Potential Contribution of Ezetimibe in NAFLD/NASH Treatment
Current Vascular Pharmacology Novel Therapeutic Targets for Phosphodiesterase 5 Inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis
Current Pharmaceutical Biotechnology Oxidative Stress Biology and Cell Injury During Type 1 and Type 2 Diabetes Mellitus
Current Neurovascular Research Identification of Functional Variants Associated with Obesity in Pakistani Kindred
Current Chinese Science Trends in Utilization of the Pharmacological Potential of Chalcones
Current Clinical Pharmacology Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms
Endocrine, Metabolic & Immune Disorders - Drug Targets The Impact of Computer Science in Molecular Medicine: Enabling High- Throughput Research
Current Topics in Medicinal Chemistry Monitoring and Surveillance of Obesity in the United States
Current Nutrition & Food Science Application of Nanotechnology in Acupuncture
Current Nanoscience Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Protecting Endothelium in Cardiovascular Diseases
Current Medicinal Chemistry Is There An Association Between Vitamin D and Hypertension?
Recent Patents on Cardiovascular Drug Discovery Purine Ionotropic (P2X) Receptors
Current Pharmaceutical Design Triamcinolone Acetonide Inhibits p38MAPK Activation and Neuronal Apoptosis in Early Diabetic Retinopathy
Current Molecular Medicine Psoriasis and Vascular Risk : An Update
Current Pharmaceutical Design Critical Illness in Obstetric Patients: Venous Thromboembolism in Pregnancy
Current Women`s Health Reviews Cognitive Function and Quality of Life in Mild Thyroid Hormone Deficiency
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Ghrelin as a Potential Anti-Obesity Target
Current Pharmaceutical Design β-cell Regenerative Potential of Selected Herbal Extracts in Alloxan Induced Diabetic Rats
Current Drug Discovery Technologies A Review Study on Prakriti (Body Constitution) Specific Herbal Tea in Diabetes Mellitus
Current Traditional Medicine Editorial (Thematic Issue: Novel Data on the Pathogenesis of Atherosclerosis, Treatment Targets, and New Therapeutic Interventions in Lipid-Related Cardiovascular Risk Factors)
Current Pharmaceutical Design