Exploring Structure-Activity Relationships with Three-Dimensional Matched Molecular Pairs-A Review.

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Matched molecular pairs (MMPs) analyze property changes based on minor structural differences in molecules.
• Traditional 2D MMPs offer valuable insights but lack spatial information.
• Three-dimensional MMPs (3D MMPs) incorporate spatial similarity for enhanced analysis.

Purpose of the Study:

• To explore the benefits and challenges of applying 3D MMPs in drug discovery.
• To understand how 3D structural information enhances traditional MMP analysis.
• To investigate the application of 3D MMPs for structure-activity relationship (SAR) studies.

Main Methods:

• Generation of molecular conformations.
• Calculation of 3D molecular superimpositions.
• Development and application of 3D similarity measures and descriptors.

Main Results:

• 3D MMPs provide detailed mechanistic insights into 2D MMP methods.
• The approach facilitates analysis of disrupted SARs and enables scaffold hopping.
• High-confidence SAR transfer between analogue series is achievable with 3D MMPs.

Conclusions:

• Incorporating 3D structural information significantly increases available data for analysis.
• Despite complexities, 3D MMPs offer substantial benefits for drug design and SAR studies.
• Various research groups are developing diverse 3D MMP models, highlighting its growing importance.