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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\u2013driven 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\u2014such as solubility, metabolic stability, and membrane permeability\u2014using 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 those exhibiting not only high binding affinity but also favorable physicochemical and ADME-related properties. Among these, we verified whether the lead compound reported in the literature was included, and confirmed that it appeared as one of the top-ranked candidates. These results demonstrate that an in silico protocol combining large-scale molecular generation, high-accuracy affinity prediction using NES, and ML-based ADME prediction enables H2L optimization that considers a broader substituent space.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10822-025-00729-7","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T03:21:00Z","timestamp":1766114460000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In silico-driven protocol for hit-to-lead optimization: a case study on PDE9A inhibitors"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8898-9316","authenticated-orcid":false,"given":"Hiroyuki","family":"Ogawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6580-7185","authenticated-orcid":false,"given":"Masateru","family":"Ohta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3199-6931","authenticated-orcid":false,"given":"Mitsunori","family":"Ikeguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"729_CR1","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1039\/B514814F","volume":"1","author":"E Hubbard","year":"2005","unstructured":"Hubbard E R (2005) 3D structure and the drug-discovery process. 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