In silico-driven protocol for hit-to-lead optimization: a case study on PDE9A inhibitors.

ABSTRACT: Hit-to-lead (H2L) optimization is a critical stage in small-molecule drug discovery, where efficient exploration of chemical space is required to identify promising lead compounds. Conventional H2L workflows rely on iterative synthesis and experimental evaluation, which limit the range of chemical space that can be explored. In contrast, in silico approaches enable efficient selection of promising compounds from a much larger chemical space by generating large numbers of virtual compounds and evaluating them computationally. To harness this potential, we developed an in silico-driven H2L protocol that integrates molecular generation, binding affinity prediction based on relative binding free energies calculated using the non-equilibrium switching (NES) method, and the evaluation of key pro

SUBMITTER: Ogawa H 

PROVIDER: S-EPMC12715073 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature