In Silico Design of Molecular Analogues of 2-Butyl-5- pentylbenzene-1,3-diol (Stemphol) as Drug Prototypes for Treatment of Chemical Dependents of Cannabis Sativa

Abstract

Background: The chemical dependency caused by recreational drug abuse is highly detrimental to humans and has direct implications for society. Cannabis sativa is still at the top of the ranking of most used drugs in the world, and its major chemical component is Δ9-THC. This molecule is the main cause of addiction in chronic users, and its action is measured by the CB1 receptor present in the CNS. So far there is no approved drug for the treatment of abstinence in C. sativa. Objective: In this sense, the objective of this research is to propose analogues of the Stemphol (2-methyl-5-pentylbenzene-1,3-diol) molecule that can serve as treatment for withdrawal crises in C. sativa addicts, initially through in silico methods. Methods: 28 structural modifications were carried out in the molecule stemphol. These were subjected to in silico predictions of pharmacokinetics, toxicology, pharmacological activity, synthetic viability and prediction of drug-receptor interaction through molecular docking. For this, the software and web servers PreADMET, DEREK 2.1, PASS, SEA, SYLVIA 2.4 and GOLD were used. Results: 22 analogues demonstrated good pharmacokinetic results and 16 analogues gave no warning of hepatotoxicity, mutagenicity, nephropathies and carcinogenicity in mammals. Biological activity predictions were performed on the PASS server, resulting in 28 analogues exhibiting adenylate cyclase inhibition and/or MAP kinase stimulating activity; in SEA, the performance of the CB1 receptor was analyzed, resulting in 20 analogues with action on CB1 receptors in humans. The selected analogues 1, 4, 16, 17, 19, 24, 25 and 26 were submitted to synthetic accessibility prediction in the SYLVIA software because they presented better results in their pharmacokinetic, toxicological and predictive properties. Conclusion: Of these, the analogues 17 and 25 obtained a very satisfactory result in the interaction with the CB1 receptor through the molecular docking method and can be considered great proposals for future in vitro and in vivo studies, with the ability to further elucidate their actions. Keywords: Chemical dependency, Cannabis sativa, Withdrawal Syndrome.