This review is devoted to the scientific achievements of the departments of organic chemistry in higher schools of Russia within the past decade.

Pharmacophore modeling is a widely used strategy for finding new hit molecules. Since not all protein targets have available 3D structures, ligand-based approaches are still useful. Currently, there are just a few free ligand-based pharmacophore modeling tools, and these have a lot of restrictions, e.g., using a template molecule for alignment. We developed a new approach to 3D pharmacophore representation and matching which does not require pharmacophore alignment. This representation can be used to quickly find identical pharmacophores in a given set. Based on this representation, a 3D pharmacophore ligand-based modeling approach to search for pharmacophores which preferably match active compounds and do not match inactive ones was developed. The approach searches for 3D pharmacophore models starting from 2D structures of available active and inactive compounds. The implemented approach was successfully applied for several retrospective studies. The results were compared to a 2D similarity search, demonstrating some of the advantages of the developed 3D pharmacophore models. Also, the generated 3D pharmacophore models were able to match the 3D poses of known ligands from their protein-ligand complexes, confirming the validity of the models. The developed approach is available as an open-source software tool: http://www.qsar4u.com/pages/pmapper.php and https://github.com/meddwl/psearch.

Nowadays, the problem of the model’s applicability domain (AD) definition is an active research topic in chemoinformatics. Although many various AD definitions for the models predicting properties of molecules (Quantitative Structure-Activity/Property Relationship (QSAR/QSPR) models) were described in the literature, no one for chemical reactions (Quantitative Reaction-Property Relationships (QRPR)) has been reported to date. The point is that a chemical reaction is a much more complex object than an individual molecule, and its yield, thermodynamic and kinetic characteristics depend not only on the structures of reactants and products but also on experimental conditions. The QRPR models’ performance largely depends on the way that chemical transformation is encoded. In this study, various AD definition methods extensively used in QSAR/QSPR studies of individual molecules, as well as several novel approaches suggested in this work for reactions, were benchmarked on several reaction datasets. The ability to exclude wrong reaction types, increase coverage, improve the model performance and detect Y-outliers were tested. As a result, several “best” AD definitions for the QRPR models predicting reaction characteristics have been revealed and tested on a previously published external dataset with a clear AD definition problem.