Abstract
Aim: We question the level of detail required in protein 3D-representation to detect site similarity which is relevant for polypharmacology prediction. Results: We modified the in-house program SiteAlign to replace generic pharmacophoric descriptors of cavity-lining amino acids by descriptors accounting for solvent exposure. Benchmarking the novel, atom-based, method (SiteAlign2) revealed no global improvement of performance. However, in the rare cases of no sequence or global structure similarities between the compared proteins, SiteAlign2 was more successful if backbone atoms are key determinants of ligand binding. Conclusion: SiteAlign suits the comparison of binding sites for close or distant homologs. SiteAlign2 provides a better insight into the physical model of site similarity between nonhomologs, but at the expense of an increased sensitivity to atomic coordinates.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.