The Mycobacterial membrane protein Large 3 (MmpL3) is a transmembrane transport protein that belongs to the resistance, nodulation, and cell division (RND) family of membrane transporters. The RND family transporters are important for the survival and pathogenesis of Mycobacterium tuberculosis (Mtb). MmpL3 was characterized to be responsible for the export of mycolic acids in the form of trehalose monomycolates (TMM) from the cytoplasm to the periplasmic space. Mycolic acids are the essential component of the outer layer of the thick and waxy cell envelope of Mtb. Accordingly, MmpL3 has emerged as a feasible molecular target for the discovery and development of new and effective medications to combat tuberculosis. Previously, we identified and reported a novel synthetic molecule 1 based on the indole-2-carboxamide scaffold (Figure 1). Further medicinal chemistry optimization of hit 1 led to the development of better and more effective derivatives 2 and 3 (Figure 1) that showed not only superior in vitro and in vivo activity but also desirable absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profile. We used molecular docking techniques to investigate the possible mode of binding of the active indole-2-carboxamides at the MmpL3. A putative homology model for the MmpL3 transporter was built using the MexB transporter as a template. While considering the limitations typical for the homology models, this computational study provided possible modes of binding and thus further insights into the structure-activity relationship of the indolecarboxamides.

Molecular docking of potent MmpL3 inhibitors based on the indole-2-carboxamide scaffold

254th National Meeting (2017)

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