Flexophore, a new versatile 3D pharmacophore descriptor that considers molecular flexibility

Area of Science:

• Computational chemistry
• Cheminformatics
• Drug discovery

Background:

• Traditional pharmacophore descriptors often overlook molecular flexibility.
• Accurate representation of molecular properties is crucial for drug discovery.

Purpose of the Study:

• To introduce Flexophore, a novel pharmacophore descriptor that incorporates molecular flexibility.
• To evaluate Flexophore's performance in virtual screening and its ability to capture chemical diversity.

Main Methods:

• Flexophore descriptor construction using enhanced MM2 atom types and conformer distributions.
• Development of a statistical comparison function based on the Cambridge Crystallographic Database.
• Virtual screening of 350 test datasets, including chemically diverse and similar molecules, against 18 biological targets.

Main Results:

• Flexophore successfully identified active molecules despite chemical dissimilarity in spiked datasets.
• Enrichment factors in complete datasets were comparable to established chemical fingerprint descriptors.
• Diversity analysis revealed that Flexophore explores chemical space orthogonal to traditional fingerprints.

Conclusions:

• Flexophore descriptor effectively captures molecular flexibility, enhancing virtual screening capabilities.
• It provides a complementary approach to chemical fingerprints for exploring chemical diversity and identifying novel bioactive compounds.