Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor

Abstract

BackgroundWe comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding.ResultsAll the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite.ConclusionsOur study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-016-0062-8) contains supplementary material, which is available to authorized users.

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

“…The hydroxyl group of Tyr547 plays an oxyanion‐stabilizing role in the catalytic mechanism of DPP‐IV, and therefore it is essential for the catalytic activity of the enzyme . Figure F shows that Tyr547 can adopt two different conformations but, in contrast with previous studies, the conformational change seems to be independent to the formation of π–π interactions with the ligand (see Figure A –D). Together with the phenyl ring of Phe357, interaction with the phenyl ring of Tyr547 is often sought to achieve nanomolar affinity, either by π–π interactions or by hydrophobic contacts with large aliphatic groups .…”

“…The superposition of the large number of experimentally validated structures available nowadays (see Supporting Information Table S2) reveals a slight flexibility of the residues of the active site with the exception of Arg358, Tyr547, and Trp629 (see Figure 3. In this regard (and according to a recent paper), 121 Figure 3E and 3F show how the Arg358 side chain has equivalent orientations regardless of the presence/absence of an inhibitor. It has also been suggested F I G U R E 1 A general overview of the structure of human DPP-IV homodimer Notes: The domain structure for one of the two subunits is also shown (with the -propeller domain in red, the / hydrolase domain in blue and the interdomain region in yellow).…”

“…In this regard (and according to a recent paper), Figure E and F show how the Arg358 side chain has equivalent orientations regardless of the presence/absence of an inhibitor. It has also been suggested that this flexibility is a consequence of the absence of water molecules around this side chain . In the case of Tyr547, two different orientations are clearly shown where the angle between the aromatic groups is around 70° .…”

“…200 that this flexibility is a consequence of the absence of water molecules around this side chain. 121 In the case of Tyr547, two different orientations are clearly shown where the angle between the aromatic groups is around 70 • . 122 According to our analysis, only one Tyr547 conformer is found at the apo form (see Figure 3E), while changes in its conformation are not always related to the formation of a -interaction with the ligand (see Figure 3C and 3D and also the following PDB complexes: 3CCC, 110 4N8E 67 , and 4N8D 67 ).…”

“…123 Two water molecules have recently been identified as being common at the binding site of 92 DPP-IV crystallized structures. 121 It has been suggested that these waters could play two different roles: (a) maintaining the proper orientation of the side chains of the Glu205/Glu206 dyad through a network via the water molecules; and (b) appropriately arranging the inhibitor at the S 2 subsite. 121…”