Fragment-Merging Strategies with Known Pyrimidine Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Dihydrofolate reductase (DHFR) is a crucial enzyme in the folate pathway, widely targeted for various therapeutic applications.
• Despite its essential role in Mycobacterium tuberculosis (Mtb) survival, Mtb DHFR remains an underexploited target for tuberculosis (TB) drug development.

Purpose of the Study:

• To design and synthesize novel compounds targeting Mtb DHFR.
• To evaluate the efficacy and binding affinity of these compounds against Mtb DHFR.
• To elucidate the binding mode of potent inhibitors using protein crystallography.

Main Methods:

• Compound design employing a merging strategy of pyrimidine-based antifolates and a unique fragment hit.
• In vitro evaluation of compound affinity against Mtb DHFR.
• Protein crystallography to determine the binding interactions of lead compounds within the Mtb DHFR active site.

Main Results:

• Four synthesized compounds exhibited high affinity for Mtb DHFR, with sub-micromolar inhibitory concentrations.
• Protein crystallography revealed that the most effective compounds bind to a previously underutilized region of the Mtb DHFR active site.

Conclusions:

• The developed compounds represent a promising new class of potential therapeutics for tuberculosis.
• Targeting Mtb DHFR with novel chemical entities, particularly those engaging unique active site regions, is a viable strategy for TB drug discovery.