PDBsum entry 4hlc

Transferase/transferase inhibitor

PDB id: 4hlc

Contents

Protein chains

195 a.a.

Ligands

T05 ×2

Waters ×296

PDB id:

4hlc

Name:

Transferase/transferase inhibitor

Title:

Sulfonylpiperidines as novel, antibacterial inhibitors of gram- positive thymidylate kinase (tmk): compound 5

Structure:

Thymidylate kinase. Chain: a, b. Fragment: tmk. Synonym: dtmp kinase. Engineered: yes

Source:

Staphylococcus aureus subsp. Aureus. Organism_taxid: 282458. Strain: mrsa252. Gene: sar0483, tmk. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.55Å R-factor: 0.180 R-free: 0.199

Authors:

A.Boriack-Sjodin,N.Olivier

Key ref:

G.Martínez-Botella et al. (2013). Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK). Bioorg Med Chem Lett, 23, 169-173. PubMed id: 23206863

Date:

16-Oct-12 Release date: 31-Oct-12

Protein chains

Q6GJI9  (KTHY_STAAR) -  Thymidylate kinase from Staphylococcus aureus (strain MRSA252)

Seq: 205 a.a.

Struc: 195 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.4.9 - dTMP kinase.
• Reaction: dTMP + ATP = dTDP + ADP

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

reference

Bioorg Med Chem Lett 23:169-173 (2013)

PubMed id: 23206863

Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).

G.Martínez-Botella, J.T.Loch, O.M.Green, S.P.Kawatkar, N.B.Olivier, P.A.Boriack-Sjodin, T.A.Keating.

ABSTRACT

Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of logD yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and >10(5) selectivity versus the human TMK homologue.