Expanding the therapeutic landscape of PDE10A inhibition through alchemical absolute binding free energy calculations and in‐vitro evaluation

In preclinical models, Phosphodiesterase-10A (PDE10A) inhibition has shown efficacy for Parkinson's and Huntington's diseases and is potentially a therapeutic approach for schizophrenia. In this study, computational approaches were employed to identify selective PDE10A inhibitors from a series of olefinated benzosuberene analogues. The molecular interactions and docking scores of the selected molecules were compared with three different co-crystal inhibitors of PDE10A. Molecular dynamics (MD) simulations confirmed the stability of the screened hit molecules with PDE10A, and AMKPD-52 was found to uniquely interact with the selectivity pocket residue Tyr-683. Further refinement using steered MD simulations and…

• CO
  Council of Scientific and Industrial Research, India

  Award: MLP0201