Pharmacophore fingerprinting. 2. Application to primary library design

Area of Science:

• Medicinal Chemistry
• Cheminformatics

Background:

• Primary library design faces challenges in selecting diverse and relevant molecular structures.
• Quantitative Structure-Activity Relationship (QSAR) studies require robust molecular descriptors for accurate predictions.

Purpose of the Study:

• To evaluate the efficacy of the pharmacophore fingerprinting (PharmPrint) methodology in primary library design.
• To develop a statistical measure for assessing the discriminating power of molecular descriptors.
• To explore the dimensionality and convergence of pharmacophoric space.

Main Methods:

• Application of the PharmPrint methodology to a reference set of bioactive molecules (MDDR9104).
• Devised a statistic to measure the discriminating power of molecular descriptors.
• Utilized Principal Component Analysis (PCA) on PharmPrint fingerprints for dimensionality reduction and visualization.
• Analyzed PCA results on subsets of classes to assess robustness.

Main Results:

• PharmPrint fingerprint demonstrated superior discriminating power compared to other molecular descriptors.
• PCA of PharmPrint fingerprints generated a low-dimensional space for visualizing molecular properties and libraries.
• PCA analysis indicated that pharmacophoric space is finite and rapidly converging, robust to new class additions.

Conclusions:

• PharmPrint is a valuable tool for addressing challenges in primary library design.
• The methodology facilitates the analysis and design of virtual combinatorial libraries.
• Pharmacophoric space appears to be a finite and converging entity, supporting efficient library design strategies.