Three-dimensional descriptors for aminergic GPCRs: dependence on docking conformation and crystal structure

Abstract

Three-dimensional descriptors are often used to search for new biologically active compounds, in both ligand- and structure-based approaches, capturing the spatial orientation of molecules. They frequently constitute an input for machine learning-based predictions of compound activity or quantitative structure-activity relationship modeling; however, the distribution of their values and the accuracy of depicting compound orientations might have an impact on the power of the obtained predictive models. In this study, we analyzed the distribution of three-dimensional descriptors calculated for docking poses of active and inactive compounds for all aminergic G protein-coupled receptors with available crystal structures, focusing on the variation in conformations for different receptors and crystals. We demonstrated that the consistency in compound orientation in the binding site is rather not correlated with the affinity itself, but is more influenced by other factors, such as the number of rotatable bonds and crystal structure used for docking studies. The visualizations of the descriptors distributions were prepared and made available online at http://chem.gmum.net/vischem_stability , which enables the investigation of chemical structures referring to particular data points depicted in the figures. Moreover, the performed analysis can assist in choosing crystal structure for docking studies, helping in selection of conditions providing the best discrimination between active and inactive compounds in machine learning-based experiments.

Keywords: Aminergic GPCRs; Crystal structure; Docking; Machine learning; Three-dimensional descriptors.

Fig. 1

Example analysis of consistency in compounds docked poses presented as the average std of all descriptors used for compounds representation

Fig. 2

Scheme of the study presented in the paper

Fig. 3

Analysis of docking results of selected compounds to crystal structures of serotonin receptor 5-HT_1B; green: active compound, red: inactive compound; D3.32 residue of the protein is visualized as sticks. (Color figure online)

Fig. 4

Example analysis of stability of docking poses for ligands of the ACM₃ receptor. Gray area refers to compounds active or inactive toward other targets considered in the study. In this case, active compounds are relatively well demarcated from the inactive ones

Fig. 5

Example visualization of the prepared online tool. Red points refer to active compounds and black to the inactive ones. Chemical structure corresponding to each data point can be manually analyzed. (Color figure online)

Fig. 6

Analysis of average std of the 3d descriptor values depending on the number of rotatable bonds in a particular compound for 5-HT_2BR ligands, when ten docked poses were taken into account