Site Identification and Next Choice Protocol for Hit-to-Lead Optimization

• Published in: Journal of Chemical Information and Modeling Vol. 64; no. 11; pp. 4475 - 4484
• Main Authors: Kudo, Genki, Hirao, Takumi, Yoshino, Ryunosuke, Shigeta, Yasuteru, Hirokawa, Takatsugu
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.06.2024; American Chemical Society (ACS)
• Subjects: Chemists; Computational Biochemistry; Datasets; Drug Design; Drug Discovery - methods; Efficiency; Error analysis; Functional groups; Molecular dynamics; Molecular Dynamics Simulation; Protein Conformation; Proteins - chemistry
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.3c02036

Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choice (SINCHO) protocol to improve the hit-to-lead efficiency. This protocol selects an anchor atom and growth site pair, which is desirable for a hit-to-lead strategy starting from a 3D complex structure. We developed and fine-tuned the protocol using a training data set and assessed it using a test data set of the preceding hit-to-lead strategy. The protocol was tested for experimentally determined structures and molecular dynamics (MD) ensembles. The protocol had a high prediction accuracy for applying MD ensembles, owing to the consideration of protein flexibility. The SINCHO protocol enables medicinal chemists to visualize and modify functional groups in a hit-to-lead manner.