Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors

Edmondson, Scott D.; Wei, Liao; Xu, Jinyou; Shang, Jackie; Xu, Shiyao; Pang, Jianmei; Chaudhary, Ashok; Dean, Dennis C.; He, Huaibing; Leiting, Barbara; Lyons, Kathryn A.; Patel, Reshma A.; Patel, Sangita; Scapin, Giovanna; Wu, Joseph K.; Beconi, Maria; Thornberry, Nancy A.; Weber, Ann E.

doi:10.1016/j.bmcl.2008.02.050

Cited by 94 publications

(38 citation statements)

References 38 publications

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“…The DPP‐IV binding site is accessible in two ways: (1) via an opening in the β‐propeller domain, or (2) via the large side opening formed at the interface of the β‐propeller and the α/β‐hydrolase domain (which is the most plausible way for substrates and inhibitors to enter or leave the binding site). PDB entry 3C45 was used to obtain this figure with the help of the Maestro program…”

Section: Dpp‐iv Binding Site Descriptionmentioning

confidence: 99%

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.

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Section: Dpp‐iv Binding Site Descriptionmentioning

confidence: 99%

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Ojeda-Montes

Gimeno

Tomás-Hernández

et al. 2018

Medicinal Research Reviews

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“…Ligands with at least one hit in the Phase search were then used in a protein-ligand rigid-docking study and docked onto the ligand binding site of the DPP-IV conformation present in the 3C45 PDB file [14]. In order to find docking poses that were compatible with the pharmacophore, the resulting ligand poses were filtered again with Phase through the structure-based common pharmacophore using the same filtering conditions as in the first Phase run but without reorienting the poses ( i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, the poses for the 4,952 compounds from the second pharmacophore screen were submitted to a shape and electrostatic-potential comparison with the experimental pose of the DPP-IV inhibitor at the PDB file 3C45 (that has the smallest IC 50 for all the non-peptide reversible inhibitors found in DPP-IV-inhibitor complexes at the PDB [14]; see Figure 1). The shape and electrostatic-potential comparison identified 446 hit molecules with potential DPP-IV inhibitory activity (see Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…During the VS, the protein-ligand docking was performed with eHiTS v2009 (SimBioSys Inc., Toronto, Canada; http://www.simbiosys.ca/ehits) [39], and ligands were docked into the ligand binding site of the DPP-IV conformation present in the 3C45 PDB file [14]. The receptor was considered to be a rigid body and the ligands as flexible such that free rotation was allowed around the single bonds of the ligand.…”

Section: Methodsmentioning

confidence: 99%

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Identification of Novel Human Dipeptidyl Peptidase-IV Inhibitors of Natural Origin (Part I): Virtual Screening and Activity Assays

et al. 2012

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BackgroundThere has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.Methodology/Principal FindingsWe predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.Conclusions/SignificanceWe have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.

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“…The fluorine substitution is extensively practiced in the design of potential molecules and therefore there is a growing demand for the synthesis of fluorinated molecules. Recently, several studies have emerged on the use of fluorinated molecules [14][15][16][17][18][19][20] as DPP-IV inhibitors, some of which are in advanced stage of development. Among them, MK-0431 (Sitagliptin, launched in the market by Merck) is a representative fluorinated DPP-IV inhibitor and its 2,4,5-trifluorophenyl moiety occupy the active pocket of DPP-IV [14].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of triazepane derivatives as DPP-IV inhibitors

Park

Jun

Shin

et al. 2009

Journal of Fluorine Chemistry

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Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors

Cited by 94 publications

References 38 publications

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Activity and selectivity cliffs for DPP‐IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening

Identification of Novel Human Dipeptidyl Peptidase-IV Inhibitors of Natural Origin (Part I): Virtual Screening and Activity Assays

Synthesis and biological evaluation of triazepane derivatives as DPP-IV inhibitors

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