Conformational sampling for large-scale virtual screening: accuracy versus ensemble size.

Area of Science:

• Computational Chemistry
• Cheminformatics

Background:

• Generating accurate molecular conformational ensembles is crucial for computer-aided drug design (CADD).
• Existing methods face challenges in balancing ensemble accuracy with computational cost, particularly for large-scale applications.
• The trade-off between the root-mean-square deviation (rmsd) to biologically active conformers and the number of conformers in an ensemble is a key consideration.

Purpose of the Study:

• To introduce the TrixX Conformer Generator (TCG), a novel tool for generating conformational ensembles.
• To address the specific requirements of large-scale CADD applications that utilize conformer databases.
• To provide a method that optimizes the balance between accuracy and ensemble size.

Main Methods:

• TCG employs a tree data structure to represent molecules and generates conformations incrementally using a best-first-search build-up process.
• Internal root-mean-square deviation (rmsd) clustering is utilized to manage the conformational space.
• Conformational energy serves as a scoring function to build ensembles of low-energy conformers, with search space coverage controlled by a user-defined quality level and molecule flexibility.

Main Results:

• Testing on 778 molecules showed that an average of 20 conformers per ensemble achieve an average accuracy of 1.13 Å.
• An exponential increase in ensemble size is required for improved accuracy (e.g., 100 conformers yield 0.99 Å accuracy).
• TCG demonstrates comparable accuracy to established tools like CATALYST and OMEGA, while offering a favorable trade-off between accuracy and ensemble size, especially for molecules with fewer than nine rotatable bonds.

Conclusions:

• TCG effectively generates conformational ensembles suitable for large-scale drug design.
• The tool provides a controllable balance between conformational accuracy and ensemble size, informed by molecule flexibility.
• TCG represents a valuable advancement in computational chemistry for drug discovery, offering competitive performance and efficient trade-offs.