Computational drug repurposing for tuberculosis by inhibiting Ag85 complex proteins

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• Tuberculosis (TB) is a deadly pulmonary infection caused by *Mycobacterium tuberculosis*.
• The *M. tuberculosis* cell envelope, particularly the Ag85 complex proteins, is crucial for drug evasion.
• Targeting the Ag85 complex offers a potential strategy to overcome drug resistance in TB.

Purpose of the Study:

• To identify existing drugs that can be repurposed to inhibit the *M. tuberculosis* Ag85 complex.
• To computationally screen a library of drugs for potential binding to Ag85 complex proteins.

Main Methods:

• Virtual screening using molecular docking (Autodock Vina) of 120 drugs against the Ag85 complex.
• Molecular dynamics simulations (Gromacs) to assess the stability of drug-protein complexes.
• Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis for drug-likeness.

Main Results:

• Three compounds—selamectin, imatinib, and eltrombopag—exhibited strong binding affinities to the Ag85 complex (–10.560 to –11.422 kcal/mol).
• Molecular dynamics simulations confirmed the stability of these complexes, with low RMSD and RMSF values.
• ADMET predictions indicated favorable drug-like properties for the identified compounds.

Conclusions:

• Selamectin, imatinib, and eltrombopag are promising candidates for drug repurposing against tuberculosis.
• Targeting the Ag85 complex with these repurposed drugs could offer a new therapeutic avenue for combating TB.