In silico and molecular dynamic simulation predictions of toxicity effects of the novel psychoactive synthetic drugs, cathinones α-PVP and 3-MMC - 25/04/25

Doi : 10.1016/j.toxac.2025.04.001

Hasnae Hoummani ^a,^b,⁎ , Soukayna Baammi ^c, Mohamed Chebaibi ^b,^d,⁎, Ibrahim Mssillou ^e, Aimad Allali ^c, Youness El Abdali ^f, Abdelkrim Agour ^e, John P. Giesy ^g,^h,ⁱ, Mourad A.M. Aboul-Soud ^j, Sanae Achour ^a,^b
^a Service of Toxico-Pharmacology, Hassan II University Hospital, Fez, Morocco
^b Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy of Fez, Sidi Mohamed Ben Abdellah University, 30000 Fez, Morocco
^c African Genome Centre (AGC), Mohammed VI Polytechnic University, Benguerir, Morocco
^d Higher Institute of Nursing Professions and Health Techniques, Ministry of Health and Social Protection, 30000 Fez, Morocco
^e Laboratory of Natural Substances, Pharmacology, Environment, Modeling, Health & Quality of Life (SNAMOPEQ), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, 30000 Fez, Morocco
^f Laboratory of Biotechnology, Environment, Agri-food and Health (LBEAS), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, 30050, Fez, Morocco
^g Department of Integrative Biology, Michigan State University, 48895 East Lansing, MI, United States
^h Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, S7N 5B3 Saskatoon, Saskatchewan, Canada
ⁱ Department of Environmental Sciences, Baylor University, 76798-7266 Waco, TX, United States
^j Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia

^⁎Corresponding author. Service of Toxico-Pharmacology, Hassan II University Hospital, sidi hrazem, Fez, Morocco.Service of Toxico-Pharmacology, Hassan II University Hospital, sidi hrazemFezMorocco

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Summary

New psychoactive substances (NPS) are synthetic compounds that mimic the effects of traditional illicit drugs and are often implicated in intoxications and drug-related incidents. Among these, synthetic cathinones, such as α-Pyrrolidinopentiophenone (α-PVP, Flakka) and 3-Methylmethcathinone (3-MMC), pose significant health risks due to their severe neuropsychiatric and cardiovascular effects. In this study, we used in silico methods to characterize α-PVP and 3-MMC and assess their pharmacological profiles and toxic potencies. The in silico study of interactions of α-PVP and 3-Methylmethcathinone 3-MMC with dopamine and serotonin transporters revealed significant binding affinities and interaction profiles. Glide scores of −7.218 and −6.698kcal/mol for α-PVP and −6.912 and −6.332kcal/mol for 3-MMC confirm their potent inhibitory activities on these transporters. Additionally, molecular dynamics simulations confirmed the stability of α-PVP and 3-MMC within dopamine and serotonin transporter binding sites. The ADME properties indicate their psychoactive potential and pharmacokinetic behaviors, with 3-MMC exhibiting higher toxicity risks than α-PVP, highlighting essential implications for public health and drug safety.

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Keywords : Psychoactive substances, α-Pyrrolidinopentiophenone, 3-Methylmethcathinone, Dopamine transporter, Serotonin transporter, Molecular docking