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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/2123
Title: Navigating the chemical space of dipeptidyl peptidase-4 inhibitors
Authors: Watshara Shoombuatong
Veda Prachayasittikul
Nuttapat Anuwongcharoen
Napat Songtawee
Teerawat Monnor
Supaluk Prachayasittikul
Virapong Prachayasittikul
Chanin Nantasenamat
Mahidol University. Faculty of Medical Technology. Center of Data Mining and Biomedical Informatics
Mahidol University. Faculty of Medical Technology. Department of Clinical Microbiology and Applied Technology
Keywords: QSAR;decision tree;scaffold analysis;fragment analysis;antidiabetic;molecular docking;rational drug design;Open Access article
Issue Date: 10-Aug-2015
Citation: Drug Design, Development and Therapy. Vol.9, 2015, 4515-4549
Abstract: This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 µM and greater than 10 µM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes.
URI: http://repository.li.mahidol.ac.th/dspace/handle/123456789/2123
metadata.dc.identifier.url: http://www.dovepress.com/navigating-the-chemical-space-of-dipeptidyl-peptidase-4-inhibitors-peer-reviewed-article-DDDT
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