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      A novel series of human dihydroorotate dehydrogenase inhibitors discovered by in vitro screening: inhibition activity and crystallographic binding mode

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          Abstract

          Human dihydroorotate dehydrogenase ( DHODH), the enzyme that catalyzes the rate‐limiting step in de novo pyrimidine biosynthesis, is considered to be an attractive target for potential treatment of autoimmune disease and cancer. Here, we present a novel class of human DHODH inhibitors with high inhibitory potency. The high‐resolution crystal structures of human DHODH complexed with various agents reveal the details of their interactions. Comparisons with the binding modes of teriflunomide and brequinar provide insights that may facilitate the development of new inhibitors targeting human DHODH.

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          The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase.

          Aaron P Davis, Matthew Pitts, Paul R. Copeland … (1996)
          The active metabolite of leflunomide. A771726, is a novel immunosuppressive compound that has been shown to be a powerful antiproliferative agent for mononuclear and T-cells. The molecular mechanism of action for this compound has not been clearly established. In vitro cellular and enzymatic assays, however, demonstrate that leflunomide is an inhibitor of several protein tyrosine kinases, with IC50 values between 30 and 100 microM. The in vivo properties of A771726 are reminiscent of another immunosuppressive agent, brequinar sodium, which has been shown to be a nonomolar inhibitor (Ki = 10-30 nM) of the enzyme dihydroorotate dehydrogenase (DHODase). On the basis, we have investigated the effects of leflunomide and A771726 on the activity of purified recombinant human DHODase. We find that A771726 is a potent inhibitor of DHODase (Ki = 179 +/- 19 nM), while the parent compound, leflunomide, had no inhibitory effect at concentrations as high as 1 microM. Studies of the dependence of inhibition on the concentrations of the substrates ubiquinone and dihydroorotate demonstrate that A771726 is a competitive inhibitor of the ubiquinone binding site and is noncompetitive with respect to dihydroorotate. The potency of A771726 as a DHODase inhibitor is thus 100-100-fold greater than that reported for its inhibition of protein tyrosine kinases. These data suggest that an alternative explanation for the immunosuppressive efficacy of A771726 may be the potent inhibition of DHODase by this compound.
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            Dual binding mode of a novel series of DHODH inhibitors.

            Johann Leban, Jan Mies, Johanna Kralik … (2006)
            Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.
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              The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites.

              Björn Walse, Veronica Tamu Dufe, Bo Svensson … (2008)
              Inhibitors of dihydroorotate dehydrogenase (DHODH) have been suggested for the treatment of rheumatoid arthritis, psoriasis, autoimmune diseases, Plasmodium, and bacterial and fungal infections. Here we present the structures of N-terminally truncated (residues Met30-Arg396) DHODH in complex with two inhibitors: a brequinar analogue (6) and a novel inhibitor (a fenamic acid derivative) (7), as well as the first structure of the enzyme to be characterized without any bound inhibitor. It is shown that 7 uses the "standard" brequinar binding mode and, in addition, interacts with Tyr356, a residue conserved in most class 2 DHODH proteins. Compared to the inhibitor-free structure, some of the amino acid side chains in the tunnel in which brequinar binds and which was suggested to be the binding site of ubiquinone undergo changes in conformation upon inhibitor binding. Using our data, the loop regions of residues Leu68-Arg72 and Asn212-Leu224, which were disordered in previously studied human DHODH structures, could be built into the electron density. The first of these loops, which is located at the entrance to the inhibitor-binding pocket, shows different conformations in the three structures, suggesting that it may interfere with inhibitor/cofactor binding. The second loop has been suggested to control the access of dihydroorotate to the active site of the enzyme and may be an important player in the enzymatic reaction. These observations provide new insights into the dynamic features of the DHODH reaction and suggest new approaches to the design of inhibitors against DHODH.
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                Author and article information

                Contributors
                Yamei Yu: yamei_yu@scu.edu.cn
                Qiang Chen:
                ORCID: https://orcid.org/0000-0002-2398-4482
                qiang_chen@scu.edu.cn
                Journal
                Journal ID (nlm-ta): FEBS Open Bio
                Journal ID (iso-abbrev): FEBS Open Bio
                Journal ID (doi): 10.1002/(ISSN)2211-5463
                Journal ID (publisher-id): FEB4
                Title: FEBS Open Bio
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2211-5463
                Publication date (Electronic): 29 May 2019
                Publication date Collection: August 2019
                Volume: 9
                Issue: 8 ( doiID: 10.1002/feb4.2019.9.issue-8 )
                Pages: 1348-1354
                Affiliations
                [ 1 ] Cancer Center West China Hospital Sichuan University and Collaborative Innovation Center of Biotherapy Chengdu China
                Author notes
                [*] [* ] Correspondence

                Q. Chen and Y. Yu, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China

                E‐mails: qiang_chen@ 123456scu.edu.cn (QC); yamei_yu@ 123456scu.edu.cn (YY)

                Author information
                https://orcid.org/0000-0002-2398-4482
                Article
                Publisher ID: FEB412658
                DOI: 10.1002/2211-5463.12658
                PMC ID: 6668370
                PubMed ID: 31087527
                SO-VID: c2e75919-77e4-4635-bd47-2f79164b475a
                Copyright © © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 04 March 2019
                Date revision received : 09 May 2019
                Date accepted : 13 May 2019
                Page count
                Figures: 4, Tables: 2, Pages: 7, Words: 3510
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 31741027
                Funded by: Sichuan Science and Technology Program
                Award ID: 2019YFH0123
                Award ID: 2019YFH0124
                Categories
                Subject: Research Article
                Subject: Research Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id feb412658
                cover-date August 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.6.2 mode:remove_FC converted:31.07.2019

                Keywords: crystal structure,dihydroorotate dehydrogenase,drug,inhibitor,pyrimidine biosynthesis
                Data availability:
                Keywords: crystal structure, dihydroorotate dehydrogenase, drug, inhibitor, pyrimidine biosynthesis

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