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Updated: May 18, 2026

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Implicit ligand theory: rigorous binding free energies and thermodynamic expectations from molecular docking
1Department of Chemistry, Duke University, Durham, North Carolina 27708, USA. dm225@duke.edu
Abstract:
A rigorous formalism for estimating noncovalent binding free energies and thermodynamic expectations from calculations in which receptor configurations are sampled independently from the ligand is derived. Due to this separation, receptor configurations only need to be sampled once, facilitating the use of binding free energy calculations in virtual screening. Demonstrative calculations on a host-guest system yield good agreement with previous free energy calculations and isothermal titration calorimetry measurements. Implicit ligand theory provides guidance on how to improve existing molecular docking algorithms and insight into the concepts of induced fit and conformational selection in noncovalent macromolecular recognition.
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