What question did this study set out to answer?

To investigate the energetics and structural conformational reorganization drug-like molecules undergo upon binding to target proteins.

April 7, 2004Journal of Medicinal Chemistry

Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding

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To investigate the energetics and structural conformational reorganization drug-like molecules undergo upon binding to target proteins.
Evaluated 150 crystal structures of pharmaceutically relevant protein-ligand complexes using multiple computational conformational analysis methods.
Calculated ligand strain energies, local energy minima status, and folding/unfolding reorganization states across bioactive conformations.
Over 60% of ligands did not bind in a local energy minimum conformation; while approximately 60% exhibited strain energies below 5 kcal/mol, at least 10% showed strain energies exceeding 9 kcal/mol.
Acceptable strain energy correlated with ligand flexibility but showed no correlation with binding affinity, with ligands generally displaying an extended conformation that exposes hydrophobic surfaces upon binding.

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Implication

Computational structural analysis reveals significant conformational strain in protein-bound drug-like ligands, indicating high reorganization energies can be tolerated without sacrificing binding...

Cite This Study

Perola et al. (2004) studied this question.

synapsesocial.com/papers/69d936fb8988aeabbe684769 https://doi.org/10.1021/jm030563w

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Implication

Computational structural analysis reveals significant conformational strain in protein-bound drug-like ligands, indicating high reorganization energies can be tolerated without sacrificing binding...

Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding

Key Points

Discussion

Implication

Cite This Study

Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding

Key Points

Discussion

Implication

Cite This Study

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