Flexible 3D alignment and its application in virtual screening

poster · 10 years ago
by Adrián Kalászi, et al (ChemAxon)

Tackling the conformational flexibility of molecular structures is an innate challenge in most molecular modeling applications ranging from pharmacophore elucidation to virtual screening. Conformational sampling is the most widely used technique to alleviate the computational complexity of modeling flexible three dimensional molecules. Though computationally tractable, yet this approach has some drawbacks.

Most importantly, it is prone to miss biologically relevant conformations. Representing flexible molecules on a continuous scale without the need of discrete sampling provides much higher degree of reliability and accuracy. But how can we address the complexity challenge and cope with the continuous flexibility within a manageable computational time frame?

A flexible 3D alignment method that overlays molecules by optimizing a potential function similar to the intersection of their molecular volumes has been developed. This method, based on the analytical representation of the conformational flexibility, is capable of aligning two or more chemical structures to very high accuracy. Nevertheless, the approach offers reasonable performance for drug-like molecules.

A generalization of the flexible conformational analysis apparatus enables the exploration of the entire conformational space of a molecule. The statistical analysis of this blurred spatial region provides a fairly low dimensional molecular descriptor which serves as the basis for a high throughput 3D virtual screening technique.