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

Genki Kudo1, Takumi Hirao2,3, Ryunosuke Yoshino3,4

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This study introduces the Site Identification and Next Choice (SINCHO) protocol to enhance drug discovery efficiency. SINCHO optimizes the hit-to-lead process by identifying key molecular sites for targeted modifications, saving time and resources.

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Area of Science:

  • Medicinal Chemistry
  • Computational Drug Discovery
  • Structural Biology

Background:

  • Drug discovery and development face significant challenges in time efficiency and cost.
  • The hit-to-lead stage is crucial for optimizing initial drug candidates but often relies on inefficient trial-and-error methods.
  • Improving the efficiency of the hit-to-lead process is vital for accelerating drug development.

Purpose of the Study:

  • To propose and validate a novel protocol, Site Identification and Next Choice (SINCHO), for enhancing hit-to-lead efficiency in drug discovery.
  • To develop a computational method that aids medicinal chemists in selecting optimal modification sites on hit compounds.
  • To improve the rational design of drug candidates by leveraging structural information and predicting growth sites.

Main Methods:

  • Development and fine-tuning of the SINCHO protocol using a training dataset.
  • Assessment of the SINCHO protocol using a test dataset from previous hit-to-lead strategies.
  • Testing the protocol's performance on both experimentally determined protein structures and molecular dynamics (MD) ensembles.
  • Evaluation of the protocol's ability to account for protein flexibility.

Main Results:

  • The SINCHO protocol demonstrated high prediction accuracy, particularly when applied to MD ensembles, due to its consideration of protein flexibility.
  • The protocol effectively identifies anchor atom and growth site pairs suitable for hit-to-lead strategies starting from 3D complex structures.
  • Validation confirmed the protocol's utility in a realistic drug discovery context.

Conclusions:

  • The SINCHO protocol offers a significant improvement in hit-to-lead efficiency for drug discovery and development.
  • By enabling visualization and modification of functional groups, SINCHO empowers medicinal chemists to make more informed decisions.
  • The protocol's high accuracy with flexible protein structures suggests its broad applicability in modern drug design pipelines.