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Fall 2022 challenge: phase 2 contenstant

Development and Evaluation of M. Tuberculosis MmpL3 Inhibitors

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

After docking the prototype in the MmpL3 (PDB 6AJG), the best pose obtained an estimated affinity interval of 1.4 – 140pM (we know that the "in vitro" MIC90 for the prototype on M. tuberculosis is about 15µM, so we are looking for something that can lower at least 100 times this result, to get results closer to the drugs already used in therapeutics). The prototype molecule was divided into three sections (head, body and tail). The Inspirator tool was used to grow the molecule separately, in the head or in the tail section. We also tried to change the core of the units (including the body), looking for the best alternatives. In the end, we obtained 160 derivatives, 54 of which had lower estimated affinity prediction than the prototype. The best result had an estimated affinity interval of 1fM – 1pM. 49 of the best derivatives were obtained from the growth/change of the head section. In this moment, the derivatives are under evaluation for synthesis possibility.
After 3 months, Mauricio has achieved the following milestones:
  1. We obtained 54 derivatives with lower estimated affinity compared to the prototype. 49 of them are growth/change of the head section of the prototype, which made clear that the body and tail sections of the prototype are already optimal. We were able to achieve our goal of lowering the estimated affinity at least 100 times (the best compound had a Hyde Estimated Affinity Lower Boundary of 1fM, 1000 times lower than the same parameter of the prototype). This milestone is considered completed now, and we are studying each of the 54 best derivatives obtained to evaluate the possibilities of synthesis.
  2. Derivatives obtained are now under synthesis evaluation
  3. This will be the last stage of the study