PDBsum entry 6tld

Hydrolase

PDB id: 6tld

Contents

Protein chains

400 a.a.

Ligands

NK5 ×4

DMF ×24

GOL ×6

Metals

_ZN ×4

__K ×8

Waters ×960

PDB id:

6tld

Name:

Hydrolase

Title:

Crystal structure of schistosoma mansoni hdac8 complexed with a triazole hydroxamate inhibitor 2

Structure:

Histone deacetylase. Chain: a, b, c, d. Engineered: yes

Source:

Schistosoma mansoni. Organism_taxid: 6183. Gene: hdac8. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.61Å R-factor: 0.167 R-free: 0.195

Authors:

T.B.Shaik,C.Romier

Key ref:

D.V.Kalinin et al. (2020). Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors. ChemMedChem, 15, 571-584. PubMed id: 31816172 DOI: 10.1002/cmdc.201900583

Date:

02-Dec-19 Release date: 18-Dec-19

Protein chains

A5H660  (A5H660_SCHMA) -  histone deacetylase from Schistosoma mansoni

Seq: 440 a.a.

Struc: 400 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1002/cmdc.201900583

ChemMedChem 15:571-584 (2020)

PubMed id: 31816172

Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors.

D.V.Kalinin, S.K.Jana, M.Pfafenrot, A.Chakrabarti, J.Melesina, T.B.Shaik, J.Lancelot, R.J.Pierce, W.Sippl, C.Romier, M.Jung, R.Holl.

ABSTRACT

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2 b (N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4-fluorophenoxy derivative 21 (1-[5-chloro-2-(4-fluorophenoxy)phenyl]-N-hydroxy-1H-1,2,3-triazole-4-carboxamide), a nanomolar smHDAC8 inhibitor (IC₅₀ =0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole-based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.