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A PLS study on the psychotropic activity for a series of cannabinoid compounds

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Abstract

Introduction

The use of the Cannabis sativa plant by man has been common for centuries due to its numerous therapeutic properties resulting from the compounds present in it, called cannabinoids. However, the use of these compounds as drugs is still limited due to the psychotropic effects caused by them. The proteins that act as receptors of cannabinoid compounds were identified and characterized, being called CB1 and CB2 receptors. There is a series of 50 cannabinoid compounds that was studied through quantum and chemometric methods in order to obtain a mathematical model that could relate the structure of these compounds to their psychotropic activity. That model proved to be effective by predicting the psychoactivity of the 50 compounds from the series and elucidating relevant characteristics that imply in psychoactivity. However, most of these 50 compounds do not have experimental data of biological activity with CB1 and CB2 receptors.

Objectives

This study aims to generate QSAR models in order to predict the biological activity of the 50 cannabinoid compounds and then relate the predicted biological activity values to the already known psychoactivity.

Methods

Another series of cannabinoid compounds was selected to generate and validate QSAR models, aiming to predict the biological activity of the 50 cannabinoid compounds with both CB1 and CB2 receptors.

Results

The PLS-CB1 and PLS-CB2 QSAR models were generated and validated in this work, proving to be highly predictive, and the biological activities (pK ) of the 50 cannabinoid compounds were predicted by them. It is important to highlight compounds Ic14, Ic18, and Ic19 (psychotropic inactive) which presented higher predicted pK values than the main cannabinoid compounds (Δ9-THC and Δ8-THC). Also, compound Ic21 stood out as the highest value of the predicted biological activities in the interaction with the CB2 receptor.

Conclusion

The generated PLS models and the predicted pKi values of the 50 cannabinoid compounds can provide valuable information in the drug design of new cannabinoid compounds that can interact with CB1 and CB2 receptors in a therapeutic way with no psychotropic effects.

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Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) (Finance Code 001), FAPESP (2016/10118–0, 2018/06680–7, 2016/24524–7, 2017/10118–0), and CNPq. Our research was carried out using the computational resources of the Center for Mathematical Sciences Applied to Industry (CeMEAI) funded by FAPESP (grant 2013/07375–0).

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Authors and Affiliations

  1. Departamento de Química E Física Molecular, Instituto de Química de São Carlos, Universidade de São Paulo, SP, 13560-970, São Carlos, Brazil

    Laise P. A. Chiari, Aldineia P. da Silva & Albérico B. F. da Silva

  2. Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, SP, 03828-000, São Paulo, Brazil

    Kathia M. Honório

Authors
  1. Laise P. A. Chiari
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  2. Aldineia P. da Silva
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  3. Kathia M. Honório
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  4. Albérico B. F. da Silva
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Laise P. A. Chiari and Aldineia P. da Silva. The first draft of the manuscript was written by Laise P. A. Chiari, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Albérico B. F. da Silva.

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This paper belongs to Topical Collection XXI - Brazilian Symposium of Theoretical Chemistry (SBQT2021)

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Chiari, L.P.A., da Silva, A.P., Honório, K.M. et al. A PLS study on the psychotropic activity for a series of cannabinoid compounds. J Mol Model 29, 46 (2023). https://doi.org/10.1007/s00894-023-05443-5

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