Molecular alignment is a critical step in 3D molecular modelling. Precise alignments are fundamental for obtaining correct and accurate results from virtual screening, scaffold hopping, pharmacophore generation and Quantitative Structure-Property Relationships (QSPR). Otherwise, the results might lead to wrong interpretations.
Superposing two structures is often easy when parts of the molecules are identical. However, finding the correct alignment is not trivial when the structures are different. Even bioactive overlays of structures that share a central scaffold do not necessarily need to overlay this central scaffold atom by atom because small changes in the molecule might affect its properties and change its position in the binding site. Existing tools that make alignments based on matching atom triplets or on field extrema are not able to capture these subtle alignment differences that ultimately have a great impact on the accuracy of the results.
Pharmacelera’s tools (PharmScreen and PharmQSAR) use state-of-the-art algorithms to maximize interaction field similarity using multiple expansion centres and tensors. This approach finds the alignments that maximize interaction field similarity regardless of the underlying molecular structure, better representing the way that compounds are positioned in the binding site.
The quality of Pharmacelera’s alignment technology was validated in a study1 that evaluated how well it reproduces the bioactive overlays of 1456 crystal structures of 121 different receptors from the AstraZeneca Overlays Validation Test Set (https://www.ccdc.cam.ac.uk/support-and-resources/downloads/) from the Cambridge Crystallographic Data Center. The study showed the advantages of using our alignment algorithm in complex datasets compared with previous studies 2.