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Fall 2021 challenge: phase 1 contenstant

Designing Itaconate Based Covalent Inhibitors for Tuberculosis: An In-silico Study

Aaron Kuriakose Prakash, Madras Christian College (University of Madras), Chennai, India

Despite decades of research invested, still Tuberculosis (TB) remains a life-threatening disease without an effective medication in market. In recent past, targeting the shallow binding sites, the covalent inhibitors are promising candidates against various 'undruggable' diseases. Inspired by inhibition efficiency of a mammalian antimicrobial metabolite Itaconate, a series of its derivatives will be prepared with CoLibri and screened. Covalent docking of promising candidates will be done on isocitrate lyase (PDB: 6XPP). Since Itaconate is a covalent inhibitor, modelling the bond making/breaking process using DFT, MD and QM/MM methods will be intriguing which in turn shed light on the mechanism of inhibition that helps us to develop efficient covalent inhibitors. Understanding the mechanism of action will play a vital role in designing new drugs. The outcomes will contribute significantly towards the ‘End TB By 2030’ strategy taken by WHO in eradicating the threat of Tuberculosis from our planet.
Aaron Kuriakose intends to achieve the following milestones:
  1. CoLibri to prepare Itaconate derivatives followed by virtual screening to find the best suitable candidate.
  2. Drug-likeness, electronic-structure characterization and covalent docking analysis to evaluate the drug and its best possible binding modes.
  3. Molecular Dynamics simulation subsequently QM/MM calculations to explore the mechanistic aspects of covalent inhibition at the active site.