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

Nevena Tomašević; Maja Vujović; Emilija Kostić; Venkatesan Ragavendran; Biljana Arsić; Sanja Lj Matić; Mijat Božović; Rossella Fioravanti; Eleonora Proia; Rino Ragno; Milan Mladenović

doi:10.3390/molecules28176236

Molecular Docking Assessment of Cathinones as 5-HT_2AR 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.

Authors

Affiliations

¹ Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, P.O. Box 60, 34000 Kragujevac, Serbia.
² Department of Pharmacy, Faculty of Medicine, University of Niš, Bulevar Dr. Zorana Đinđića 81, 18000 Niš, Serbia.
³ Department of Physics, Sri Chandrasekharendra Saraswathi Viswa Mahavidyalaya, Kanchipuram 631561, Tamil Nadu, India.
⁴ Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
⁵ Department of Science, Institute for Informational Technologies, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia.
⁶ Faculty of Science and Mathematics, University of Montenegro, Džordža Vašingtona bb, 81000 Podgorica, Montenegro.
⁷ Department of Drug Chemistry and Technology, Faculty of Pharmacy and Medicine, Rome Sapienza University, P.le A. Moro 5, 00185 Rome, Italy.
⁸ Rome Center for Molecular Design, Department of Drug Chemistry and Technology, Faculty of Pharmacy and Medicine, Rome Sapienza University, P.le A. Moro 5, 00185 Rome, Italy.

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-HT_2AR, 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-HT_2AR binder prior to experimental evaluation. The obtained models, which showed a good agreement with the chemical properties of co-crystallized 5-HT_2AR ligands, proved to be valuable for future virtual screening campaigns to recognize unused cathinones and similar compounds, such as 5-HT_2AR 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).