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December 8, 2025Journal of Chemical Theory and ComputationOpen Access

Sampling High-Dimensional Conformational Free Energy Landscapes of Active Pharmaceutical Ingredients

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Authors

MSMatteo Salvalaglio

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Overview

Our approach identifies conformational preferences of bicalutamide, demonstrating implications for drug design and crystallographic data interpretation.

Key Points

  • To develop a method for computing high-dimensional conformational free energy surfaces of flexible molecules.
  • Utilized a gridless framework combining well-tempered metadynamics with Density Peaks Advanced clustering.
  • Applied local density estimation for energy assignment on a per-configuration basis.
  • Validated the method by reproducing alanine dipeptide's free energy surface.
  • Identified solvent-dependent conformational preferences of bicalutamide in varied solvents.
  • Demonstrated scalability in exploring high-dimensional torsional angle spaces.
  • Predicted conformational shifts in agreement with known crystallographic data.

Cite This Study

Matteo Salvalaglio (2025) studied this question.

synapsesocial.com/papers/693624ce4fa91c937236cd5fhttps://doi.org/10.1021/acs.jctc.5c01247
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