Dataset Information

Fragment-Based De?Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.

ABSTRACT: Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted de?novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best-in-class HtrA inhibitor. The results obtained reinforce the validity of ligand-based de?novo design and binding-kinetics-guided optimization for the efficient discovery of pioneering lead structures and prototyping drug-like chemical probes with tailored bioactivity.

SUBMITTER: Perna AM

PROVIDER: S-EPMC6311382 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.

Perna Anna M AM Rodrigues Tiago T Schmidt Thomas P TP Böhm Manja M Stutz Katharina K Reker Daniel D Pfeiffer Bernhard B Altmann Karl-Heinz KH Backert Steffen S Wessler Silja S Schneider Gisbert G

Angewandte Chemie (International ed. in English) 20150609 35

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best-in-class HtrA inhibitor. The results obtained rein ...[more]

PMID: 26069090

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Project description:Dihydroneopterin aldolase (DHNA) is essential for folate biosynthesis in microorganisms. Without a counterpart in mammals, DHNA is an attractive target for antimicrobial agents. Helicobacter pylori infection occurs in human stomach of over 50% of the world population, but first-line therapies for the infection are facing rapidly increasing resistance. Novel antibiotics are urgently needed, toward which structural information on potential targets is critical. We have determined the crystal structure of H. pylori DHNA (HpDHNA) in complex with a pterin molecule (HpDHNA:Pterin) at 1.49-Å resolution. The HpDHNA:Pterin complex forms a tetramer in crystal. The tetramer is also observed in solution by dynamic light scattering and confirmed by small-angle X-ray scattering. To date, all but one reported DHNA structures are octameric complexes. As the only exception, ligand-free Mycobacterium tuberculosis DHNA (apo-MtDHNA) forms a tetramer in crystal, but its active sites are only partially formed. In contrast, the tetrameric HpDHNA:Pterin complex has well-formed active sites. Each active site accommodates one pterin molecule, but the exit of active site is blocked by two amino acid residues exhibiting a contact distance of 5.2 Å. In contrast, the corresponding contact distance in Staphylococcus aureus DHNA (SaDHNA) is twice the size, ranging from 9.8 to 10.5 Å, for ligand-free enzyme, the substrate complex, the product complex, and an inhibitor complex. This large contact distance indicates that the active site of SaDHNA is wide open. We propose that this isozyme-specific contact distance (ISCD) is a characteristic feature of DHNA active site. Comparative analysis of HpDHNA and SaDHNA structures suggests a fragment-based strategy for the development of isozyme-specific inhibitors. Graphical abstract Image 1 Highlights • Crystal structure of Helicobacter pylori DHNA in complex with pterin at 1.49 Å.• H. pylori DHNA exists as a tetramer in crystal with well-formed active sites.• The tetrameric H. pylori DHNA assembly also exits in solution.• Structural comparison reveals an isozyme-specific feature of DHNA active sites.• H. pylori DHNA structure suggests a strategy for isozyme-specific inhibitor design.

Dataset Information

Fragment-Based De?Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.

Publications

Fragment-Based De Novo Design Reveals a Small-Molecule Inhibitor of Helicobacter Pylori HtrA.

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