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Updated: Aug 20, 2026

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Reverse-docking as a computational tool for the study of asymmetric organocatalysis
D Joseph Harriman1, Ghislain Deslongchamps
1Department of Chemistry, University of New Brunswick, Fredericton, New Brunswick, Canada E3B 5A3.
Abstract:
A novel methodology for 'reverse-docking' a cationic peptide-based organocatalyst to a rigid anionic transition state (TS) model for the conjugate addition of azide to alpha,beta-unsaturated carbonyl substrates is described. The resulting docking poses serve as simplified TS models for enantioselective catalysis. Molecular mechanics-based scoring and ranking of the docking poses, followed by clustering and structural analysis, reveal a clear energetic preference for docking to the S-enantiomeric azidation TS model, in agreement with experiment. Clear energetic trends emerged from docking the catalyst to both enantiomers of all six azidation TS models of this study. Structural analysis of the most favorable pose suggests a mechanism for enantioselective catalysis that is consistent with principles of molecular recognition, catalysis, and experimental data.
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