Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• The Cambridge Structural Database (CSD) and Protein Data Bank (PDB) are crucial resources for understanding molecular structures.
• Conformation preferences of druglike molecules are essential for effective drug design.
• Existing literature provides a foundation for analyzing molecular conformations.

Purpose of the Study:

• To present conformation preferences of druglike molecules based on torsion angle distributions.
• To demonstrate the relevance of the Cambridge Structural Database (CSD) for drug design.
• To review and highlight preferred conformations of various chemical substructures.

Main Methods:

• Analysis of torsion angle distributions from frequently occurring molecular substructures.
• Comparison of substructures from clinical trial compounds, CSD, and PDB ligands.
• In-depth discussion of aryl ring substituents, biaryl systems, and acyclic linkages.
• Examination of six- and seven-membered ring systems and sulfur-oxygen contacts.

Main Results:

• Preferred conformations for elementary acyclic systems and sulfonamides were identified.
• Properties of aryl ring substituents and biaryl systems were analyzed in detail.
• Torsion angle histograms from CSD and PDB structures were compared for selected motifs.
• Attractive sulfur-oxygen contacts were discussed as a key feature.

Conclusions:

• The study provides valuable insights into conformation preferences critical for drug design.
• The CSD is a relevant database for drug design, complementing PDB data.
• Understanding these conformational preferences can guide the development of novel therapeutics.