DESIGN AND DFT STUDY OF NOVEL SQ109 DERIVATIVES AS POTENTIAL INHIBITORS OF MMPL3 PROTEIN USING IN SILICO TECHNIQUES FOR THE TREATMENT OF MULTI DRUGRESISTANT TUBERCULOSIS

Abstract

Background: The increasing incidence of multidrug-resistant tuberculosis highlight the vital need for novel anti tubercular agents that act through novel molecular mechanisms. Mycobacterial membrane MmpL3, crucial transporter involved in mycolic acid transport and mycobacterial cell-wall biosynthesis, has gained prominence as a promising therapeutic target. Method: Seven novel SQ109 derivative (SS1-SS7) were rationally designed and evaluated using an  integrated in silico approach. Molecular docking studies were performed to investigate their binding affinity and interaction patterns within the active binding site of MmpL3. The molecular interactions of the designed derivatives with key amino acid residues were analyzed to assess their binding stability. Density functional theory (DFT) calculations were executed for the lead compounds to explore its electronic properties, molecular stability and chemical reactivity of these compounds. Results: The designed derivatives, SS2 manifested the highest docking score, signifying a favorable binding affinity against MmpL3 compared with the comparative compound SQ109. Associated analysis showed that SS2 established substantial hydrophobic and hydrogen-bonding interaction with key amino acid target site residue within the binding site, which may promote its enhanced binding stability. DFT analysis of SS2 explained established a suitable HOMO LUMO energy gap, Promising ionization potential, and a low electrophilicity index, showing good molecular stability and potentially reduced chemical reactivity. Discussion: The computational results indicate the designed derivative of SS2 could bind efficiently within the MmpL3 binding pocket through significant hydrophobic and hydrogen-bonding interactions, signifying its potential as a promising SQ109-derived anti-tubercular compound. The DFT analysis also show favourable electronic stability and sensible chemical reactivity, further supporting SS2 as a potential lead candidate for advance investigation. Conclusion: The comprehensive computational findings identify the SS2 as a exhibiting lead compound targeting MmpL3 and provide a rational basis for its further investigate as a potential anti-tubercular agent against MDR-TB. Experimental validation, including in vitro antimicrobial evaluation and further pharmacological studies, is warranted to confirm its therapeutic potential.