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 properties-such as solubility, metabolic stability, and membrane permeability-using machine learning (ML) techniques. In this study, within the context of H2L optimization, we examined the applicability, accuracy, and utility of NES, a relatively new high-precision binding free energy calculation method, and evaluated its effectiveness in large-scale exploration of substituent space. The phosphodiesterase 9A inhibitor was used as a model system. Starting from the reported high-throughput screening hit compound, we first modified the core structure and then sequentially conducted large-scale exploration of two substitution sites. Following this protocol, we narrowed down compounds predicted to…
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