Molecular Docking Assessment of Cathinones as 5-HT2AR Ligands: Developing of Predictive Structure-Based Bioactive Conformations and Three-Dimensional Structure-Activity Relationships Models for Future Recognition of Abuse Drugs

Molecules. 2023 Aug 24;28(17):6236. doi: 10.3390/molecules28176236.

Abstract

Commercially available cathinones are drugs of long-term abuse drugs whose pharmacology is fairly well understood. While their psychedelic effects are associated with 5-HT2AR, the enclosed study summarizes efforts to shed light on the pharmacodynamic profiles, not yet known at the receptor level, using molecular docking and three-dimensional quantitative structure-activity relationship (3-D QSAR) studies. The bioactive conformations of cathinones were modeled by AutoDock Vina and were used to build structure-based (SB) 3-D QSAR models using the Open3DQSAR engine. Graphical inspection of the results led to the depiction of a 3-D structure analysis-activity relationship (SAR) scheme that could be used as a guideline for molecular determinants by which any untested cathinone molecule can be predicted as a potential 5-HT2AR binder prior to experimental evaluation. The obtained models, which showed a good agreement with the chemical properties of co-crystallized 5-HT2AR ligands, proved to be valuable for future virtual screening campaigns to recognize unused cathinones and similar compounds, such as 5-HT2AR ligands, minimizing both time and financial resources for the characterization of their psychedelic effects.

Keywords: 3-D QSAR; 5-HT2AR; cathinones; molecular docking.

MeSH terms

  • Hallucinogens* / pharmacology
  • Illicit Drugs*
  • Ligands
  • Molecular Docking Simulation
  • Quantitative Structure-Activity Relationship
  • Serotonin

Substances

  • cathinone
  • Serotonin
  • Hallucinogens
  • Ligands
  • Illicit Drugs

Grants and funding

This work was supported by the Serbian Ministry of Science, Technological Development, and Innovation (Agreement Nos. 451-03-47/2023-01/200122 and 451-03-47/2023-01/200378), and supported by two grants from Progetti di Ricerca di Università 2015, Sapienza Università di Roma (C26A15RT82 and C26A15J3BB).