Integration of virtual screening and susceptibility test to discover active-site subpocket-specific biogenic inhibitors of Helicobacter pylori shikimate dehydrogenase

International Microbiology : the Official Journal of the Spanish Society for Microbiology
Kuifeng WangJiansheng Zhu

Abstract

Shikimate dehydrogenase (HpSDH) (EC 1.1.1.25) is a key enzyme in the shikimate pathway of Helicobacter pylori (H. pylori), which catalyzes the NADPH-dependent reversible reduction of 3-dehydroshikimate to shikimate. Targeting HpSDH has been recognized as an attractive therapeutic strategy against H. pylori infection. Here, the catalytic active site in the crystal structure of HpSDH in complex with its substrate NADPH and product shikimate was examined in detail; the site can be divided into three spatially separated subpockets that separately correspond to the binding regions of shikimate, NADPH dihydronicotinamide moiety, and NADPH adenine moiety. Subsequently, a cascading protocol that integrated virtual screening and antibacterial test was performed against a biogenic compound library to identify biologically active, subpocket-specific inhibitors. Consequently, five, eight, and six promising compounds for, respectively, subpockets 1, 2, and 3 were selected from the top-100 docking-ranked hits, from which 11 compounds were determined to have high or moderate antibacterial potencies against two reference H. pylori strains, with MIC range between 8 and 93 μg/mL. It is found that the HpSDH active site prefers to accommodate amph...Continue Reading

References

Nov 1, 1972·Proceedings of the National Academy of Sciences of the United States of America·B N AmesH Bartsch
Oct 23, 1997·Clinical Microbiology Reviews·B E DunnM J Blaser
May 6, 1998·Protein Science : a Publication of the Protein Society·D M Lorber, B K Shoichet
Jan 6, 1999·Journal of Pharmaceutical Sciences·J D IrvineJ R Grove
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
May 29, 2003·Current Topics in Medicinal Chemistry·Jing LinSteven M Winter
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jan 26, 2005·Journal of Chemical Information and Modeling·John J Irwin, Brian K Shoichet
Jun 28, 2005·Nucleic Acids Research·John C GordonAlexey Onufriev
Jul 19, 2006·Clinical Microbiology Reviews·Johannes G KustersErnst J Kuipers
Feb 11, 2009·Antimicrobial Agents and Chemotherapy·Ronita DeAsish K Mukhopadhyay
Aug 26, 2010·Journal of Chemical Information and Modeling·Michael M Mysinger, Brian K Shoichet
May 17, 2012·Nucleic Acids Research·Chi Ho NganSandor Vajda
Sep 12, 2012·World Journal of Gastrointestinal Pharmacology and Therapeutics·Vincenzo De FrancescoAngelo Zullo
Mar 19, 2014·Journal of Biomolecular Screening·James PeekDinesh Christendat
Apr 15, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Claudia Avitia-DomínguezAlfredo Téllez-Valencia
May 16, 2014·Journal of Molecular Modeling·Feifei TianPeng Zhou
Jul 8, 2014·Journal of Chemical Information and Modeling·Hua YuZhicai Shang
Feb 3, 2015·Journal of Chemical Information and Modeling·Chao YangPeng Zhou
Feb 1, 2012·Molecular Informatics·Nadine Homeyer, Holger Gohlke
May 26, 2018·Future Microbiology·Ayla Debraekeleer, Han Remaut

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Citations

Nov 23, 2019·Journal of Receptor and Signal Transduction Research·Linlin XuNaizhou Guo

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Methods Mentioned

BETA
dissection

Software Mentioned

PreADMET
PBSA
FTMAP
REDUCE
AMBER

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