Shared Binding Mode of Perrottetinene and Tetrahydrocannabinol Diastereomers inside the CB1 Receptor May Incentivize Novel Medicinal Drug Design: Findings from an in Silico Assay Matheus Henrique Reis, Deborah Antunes,* Lucianna H. S. Santos, Ana Carolina Ramos Guimarã es, and Ernesto Raul Caffarena Cite This: https://dx.doi.org/10.1021/acschemneuro.0c00547 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: In recent years, therapeutic compounds derived from phytocannabinoids have brought renewed attention to the benefits they offer to ameliorate chronic disease symptoms. Among cannabinoids, tetrahydrocannabinol (THC) is a well-known component of the Cannabis plant, whose active principles have been studied through the years. Another psychoactive phytocan- nabinoid, derived from liverworts Radula, perrottetinene (PET), has created interest, especially as a pharmaceutical product and for its legal recreational use. Unfortunately, so far, the interaction mode of these compounds at the type 1 cannabinoid receptors (CB1R) binding site remains unknown, and no experimental three- dimensional structure in complex with THC or PET is available in the Protein Data Bank. Today, many computational methodologies can assist in this crusade and help unveil how these molecules bind, based on the already known pose of a structurally similar compound. In this work, we aim to elucidate the binding mode of THC and PET molecules in both cis and trans conformers, using a combination of several computational methodologies, including molecular docking, molecular dynamics, free energy calculations, and protein-energy network studies. We found that THC and PET interact similarly with the CB1R, in a different conformation depending on the considered diastereomer. We have observed that cis ligands adopted a half-chair conformation of the cycle ring containing the dimethyl group, assuming an axial or equatorial conformation producing a different induced fitting of the surrounding residues compared with trans ligands, with higher interaction energy than the trans conformer. For PET, we have seen that Trp-279 and Trp-356 have a marked influence on the binding. After binding, Trp-279 accommodates its side chain to better interact with the PET’s terminal phenyl group, disturbing CB1R residues communication. The interaction with Trp-356 might impair the activation of CB1R and can influence the binding of PET as a partial agonist. Understanding the PET association with CB1R from a molecular perspective can offer a glimpse of preventing potential toxicological or recreational effects since it is an attractive lead for drug development with fewer side effects than trans-THC. KEYWORDS: Phytocannabinoids, tetrahydrocannabinol, perrottetinene, binding mode, molecular docking, molecular dynamics simulations, free energy calculations ■ INTRODUCTION In the last years, the medicinal industry has been developing an increasing interest in the therapeutic properties of derivatives of Cannabis sativa, the principal source of phytocannabinoids, and the endocannabinoid system (ECS) based on experimental evidence of their applications in medical prescriptions and recreational activities. The ECS in humans comprises endogenous cannabinoids (endocannabinoids), synthesis/ degradation enzymes, and cannabinoid receptors, which are involved in the regulation of several functions such as appetite, obesity, pain, and inflammation. 1,2 The Δ 9 -trans-tetrahydrocannabinol (trans-THC) is the major chemical component of Cannabis sativa, isolated and synthesized in 1964 by Gaoni and Mechoulam, and is also the most potent natural partial agonist targeting cannabinoid receptors. 3 Since phytocannabinoids interact with these receptors, they can be involved in the endocannabinoid tone (the general function of ECS). Finding new cannabimimetic compounds, i.e., phytochemicals and secondary metabolites capable of interacting with the ECS, offers new alternatives for exploring novel therapeutic receptor agonists or antagonists Received: August 19, 2020 Accepted: November 5, 2020 Research Article pubs.acs.org/chemneuro © XXXX American Chemical Society A https://dx.doi.org/10.1021/acschemneuro.0c00547 ACS Chem. Neurosci. XXXX, XXX, XXX-XXX Downloaded via SAN FRANCISCO STATE UNIV on November 20, 2020 at 08:56:49 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.