PDBsum entry 5ngr

Hydrolase

PDB id: 5ngr

Contents

Protein chains

154 a.a.

Ligands

8WT ×2

SO4 ×6

Waters ×79

PDB id:

5ngr

Name:

Hydrolase

Title:

Crystal structure of human mth1 in complex with fragment inhibitor 8- (methylsulfanyl)-7h-purin-6-amine

Structure:

7,8-dihydro-8-oxoguanine triphosphatase. Chain: a, b. Fragment: unp residues 42-197. Synonym: 2-hydroxy-datp diphosphatase,8-oxo-dgtpase,nucleoside diphosphate-linked moiety x motif 1,nudix motif 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nudt1, mth1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.20Å R-factor: 0.213 R-free: 0.254

Authors:

R.Gustafsson,A.Rudling,I.Almlof,E.Homan,M.Scobie,U.Warpman Berglund, T.Helleday,J.Carlsson,P.Stenmark

Key ref:

A.Rudling et al. (2017). Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space. J Med Chem, 60, 8160-8169. PubMed id: 28929756 DOI: 10.1021/acs.jmedchem.7b01006

Date:

20-Mar-17 Release date: 04-Oct-17

Protein chains

P36639  (8ODP_HUMAN) -  Oxidized purine nucleoside triphosphate hydrolase from Homo sapiens

Seq: 156 a.a.

Struc: 154 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.6.1.- - ?????
• Enzyme class 3: E.C.3.6.1.56 - 2-hydroxy-dATP diphosphatase.
• Reaction: 2-oxo-dATP + H2O = 2-oxo-dAMP + diphosphate + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1021/acs.jmedchem.7b01006

J Med Chem 60:8160-8169 (2017)

PubMed id: 28929756

Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space.

A.Rudling, R.Gustafsson, I.Almlöf, E.Homan, M.Scobie, U.Warpman Berglund, T.Helleday, P.Stenmark, J.Carlsson.

ABSTRACT

Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC₅₀values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.