Insights into the Inhibition of Mycolic Acid Synthesis by Cytosporone E Derivatives for Tuberculosis Treatment Via an In Silico Multi-target Approach

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a major global health threat. The treatment of TB is hampered by the emergence of multidrug resistance, so there is an urgent need to discover new anti-tubercular agents. Multi-target anti-tubercular agents targeting key proteins involved in mycolic acid biosynthesis represent an effective approach to combat TB. This study used a multi-target computational approach to probe the inhibitory potential of 18 cytosporone E analogues against vital proteins involved in Mtb mycolic acid synthesis (InhA, KasA, and MmpL3) utilizing the Schrodinger suite. Among these, 17 cytosporone E derivatives displayed docking scores ranging from - 8.677 to - 4.617 kcal/mol, which were better than the reference TLM6 (- 3.477 kcal/mol) in KasA. While 7 compounds (1-7) showed higher binding affinity (- 12.418 to - 10.103 kcal/mol) than the InhA co-crystallized ligand AP-124 (- 9.866 kcal/mol) and significant binding (- 9.647 to - 7.279 kcal/mol) against MmpL3. The reference ligand SQ109 showed the highest docking score (- 12.786 kcal/mol) in MmpL3. The seven shortlisted compounds showed acceptable MM-GBSA free binding energy against the three proteins. Further, compounds 1-4 were studied by molecular dynamics (MD) simulations for 100 n and density functional theory (DFT) calculations. Compounds 1-4 and protein showed an average RMSD below 3 angstrom, reflecting the stability of the compounds with InhA protein. The compounds' order of increased reactivity and photo-stability according to the DFT data are as follows 1 > 3 > 2 > 4. Also, compounds 1-4 showed favorable ADMET properties (absorption, distribution, metabolism, excretion, and toxicity). Thus, these compounds may be considered for further experimental testing to confirm their potential anti-tubercular activity.

Automated summary

This study investigated the inhibitory potential of 18 cytosporone E analogues against proteins involved in mycolic acid synthesis in Mycobacterium tuberculosis. Several compounds showed better binding affinity and stability than reference compounds, and four compounds displayed favorable pharmacokinetic properties. These findings suggest that these compounds may have potential anti-tubercular activity.