Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?

Area of Science:

• Computational chemistry
• Drug discovery
• Medicinal chemistry

Background:

• Conformational flexibility is crucial for macrocycles and beyond rule of 5 (bRo5) drugs.
• Accurate conformational prediction is vital for designing drugs in the bRo5 space.

Purpose of the Study:

• To evaluate three conformational sampling tools: OMEGA, MOE-LowModeMD (MOE), and MacroModel (MC).
• To assess their performance in predicting conformations for 10 bRo5 drugs and clinical candidates in polar and apolar environments.

Main Methods:

• Conformational sampling using OMEGA, MOE, and MC.
• Analysis of generated conformer ensembles in polar and apolar solvents.
• Comparison of sampled conformers with experimental data (crystal structures, NMR).

Main Results:

• OMEGA generated ensembles spanning larger structural and property spaces than MOE and MC.
• OMEGA and MC, but not MOE, produced distinct ensembles in polar versus apolar environments.
• All tools reproduced crystal structure conformers for 9/10 compounds; OMEGA showed slightly better performance.
• OMEGA successfully identified roxithromycin conformers observed in both aqueous and chloroform solutions.

Conclusions:

• OMEGA is a robust tool for conformational sampling of bRo5 drugs.
• Molecular descriptors (e.g., radius of gyration, polar surface area) are preferred over energy or RMSD for selecting biologically relevant conformers in bRo5 drug discovery.