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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Authors

EPEmanuele PerolaBlueprint Medicines (United States)PCPaul S. CharifsonDrug Discovery Laboratory (Norway)

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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...

Key Points

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.

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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