Dual-targeted hit identification using pharmacophore screening

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Molecular Biology

Background:

• Tuberculosis (TB) remains a significant global health threat, exacerbated by rising antibiotic resistance.
• Developing novel therapeutic strategies is crucial to overcome drug-resistant Mycobacterium tuberculosis strains.
• Dual/multi-target drug discovery presents a viable approach to combat bacterial resistance effectively.

Purpose of the Study:

• To identify novel compounds that simultaneously inhibit two key enzymes in Mycobacterium tuberculosis: leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS).
• To explore the potential of dual-target inhibitors in overcoming antibiotic resistance in tuberculosis treatment.

Main Methods:

• Construction of ligand-based pharmacophore models.
• Pharmacophore screening to identify potential hit compounds.
• In vitro aminoacylation assays to evaluate enzyme inhibition.
• Molecular modeling studies to assess binding modes.

Main Results:

• Five compounds from diverse chemical classes were identified as inhibitors of both LeuRS and MetRS.
• Compound 1, 3-(3-chloro-4-methoxy-phenyl)-5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-ylamine, exhibited potent inhibition with IC50 values of 13 µM for LeuRS and 13.8 µM for MetRS.
• Molecular modeling revealed that compound 1 binds to the active sites of both enzymes in a similar manner.

Conclusions:

• The identified compounds, particularly compound 1, show promise as starting points for developing new antituberculosis agents.
• Dual-target inhibition of LeuRS and MetRS is a feasible strategy for combating drug-resistant tuberculosis.
• Further chemical optimization of these compounds could lead to effective new therapies against tuberculosis.