Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Lipoamide dehydrogenase (Lpd) from Mycobacterium tuberculosis (Mtb) is crucial for virulence and a validated target for tuberculosis (TB) treatment.
• Despite extensive screening, only two inhibitor series for Mtb Lpd have been discovered, highlighting the need for novel chemical matter.
• Advancements in virtual screening and compound libraries offer new avenues for identifying potential TB therapeutics.

Purpose of the Study:

• To identify novel chemical inhibitors of Mtb Lpd by screening a large virtual library.
• To expand the chemical diversity beyond existing sulfonamide inhibitors.
• To validate and optimize newly discovered Mtb Lpd inhibitors.

Main Methods:

• Large-scale virtual screening of the Enamine REAL library (∼1.12 billion compounds) using GPU Shape screening against Mtb Lpd.
• Identification and characterization of inhibitor compounds based on IC50 values.
• Potency optimization of lead compounds and co-crystallization for structural analysis.

Main Results:

• Six new Mtb Lpd inhibitors were identified with IC50 values ranging from 5-100 μM.
• The identified inhibitors showed some structural diversity in their core scaffolds, expanding on known sulfonamide series.
• Two potent inhibitors were optimized to submicromolar potency, and a co-crystal structure of an optimized analogue (TDI-13537) was obtained.

Conclusions:

• GPU Shape screening of large compound libraries is effective for discovering novel Mtb Lpd inhibitors.
• The identified compounds represent new chemical matter that can be further developed for tuberculosis treatment.
• Structural insights from TDI-13537 provide a basis for understanding and improving inhibitor potency.