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Fall 2022 challenge: phase 1 contenstant

Development and Evaluation of M. Tuberculosis MmpL3 Inhibitors

Mauricio Homem-de-mello, Universidade de Brasilia, Brasilia, Brazil

The mycobacterial membrane protein large 3 (MmpL3) transporter is a protein present in Mycobacteria species and is required for the transport of trehalose monomycolates across the cell membrane for cell-wall biosynthesis, thus making it a promising target for drugs. Some compounds have already been identified as inhibitors of the MmpL3 transporter and, therefore, can suppress mycobacterial growth. However, resistance development and the need for more active compounds (with higher affinity) are important propellers for researching new molecules. Our group has already identified one active compound derived from the chemical hybridization of two known ligands of MmpL3. In this project, we will develop new and more active molecules using SeeSAR functionalities to evaluate the binding site and the influence of chemical fragments insertion on our compound. The best results will be synthesized, purified, and tested in vitro against M. tuberculosis strains with different resistance patterns.
Mauricio intends to achieve the following milestones:
  1. In silico development and evaluation of the MmpL3 ligands based on an active hybrid compound
  2. Synthesis and purity evaluation of the best in silico results
  3. Biological evaluation (Minimal Inhibitory Concentration) of the synthetic compounds