Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design and Analysis of Pharmacokinetics, Pharmacodynamics and Toxicological Analysis of Cannabidiol Analogs using In Silico Tools

Author(s): Carlos Roberto Mendes Júnior and Eduardo Damasceno Costa*

Volume 19, Issue 10, 2022

Published on: 01 April, 2022

Page: [897 - 904] Pages: 8

DOI: 10.2174/1570180819666220202151959

Price: $65

conference banner
Abstract

Background: Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis Sativa, has become an interesting option for medicinal chemists in the development of new drug candidates.

Objective: This study aims to propose analogs with therapeutic potential from the CBD scaffold.

Methods: The 16 analogs proposed were designed using the PubChem Sketcher V. 2.4® software. Already, CBD analogs were subjected to different in silico tools, such as Molinspiration®; SwissADME®; SwissTargetPrediction®, and OSIRIS Property Explorer®.

Results and Discussion: The screening of CBD analogs carried out in this study showed compounds 9 and 16 with a good affinity for interactions with CB1 and CB2 receptors. Pharmacokinetic data showed that these two compounds have good oral absorption. Finally, in silico toxicity data showed that these compounds pose no risk of a toxic event in humans.

Conclusion: CBD analogs 9 and 16 would have a better profile of drug candidates to be further tested in vitro and in vivo models.

Keywords: Cannabidiol, in silico screening, Cannabis sativa, ADMET predictions, physical-chemical properties, CBD analogs.

« Previous Next »
Graphical Abstract

[1]
Chan, H.C.S.; Shan, H.; Dahoun, T.; Vogel, H.; Yuan, S. Advancing drug discovery via artificial intelligence. Trends Pharmacol. Sci., 2019, 40(8), 592-604.
[http://dx.doi.org/10.1016/j.tips.2019.06.004]
[2]
van Wijk, R.C.; Alsoud, R.A.; Lennernäs, H.; Simonsson, U.S.H. Model-informed drug discovery and development strategy for the rapid development of anti-tuberculosis drug combinations. In: Appl. Sci., 2020, 10, 2376.
[http://dx.doi.org/10.3390/app10072376]
[3]
Issa, N.T.; Wathieu, H.; Ojo, A.; Byers, S.W.; Dakshanamurthy, S. Drug metabolism in preclinical drug development: A survey of the discovery process, toxicology, and computational tools. Curr. Drug Metab., 2017, 18(6), 556-565.
[http://dx.doi.org/10.2174/1389200218666170316093301] [PMID: 28302026]
[4]
Kazmi, S.R.; Jun, R.; Yu, M.S.; Jung, C.; Na, D. In silico approaches and tools for the prediction of drug metabolism and fate: A review. Comput. Biol. Med., 2019, 106, 54-64.
[http://dx.doi.org/10.1016/j.compbiomed.2019.01.008]
[5]
Fernández, Ó. THC:CBD in daily practice: Available data from UK, Germany and Spain. Eur. Neurol., 2016, 75(Suppl. 1), 1-3.
[http://dx.doi.org/10.1159/000444234]
[6]
Ghabrash, M.F. Cannabidiol for the treatment of psychosis among patients with schizophrenia and other primary psychotic disorders: A systematic review with a risk of bias assessment. Psychiatry Res., 2020, 286, 112890.
[http://dx.doi.org/10.1016/j.psychres.2020.112890]
[7]
Chanda, D.; Neumann, D.; Glatz, J.F.C. The endocannabinoid system: Overview of an emerging multi-faceted therapeutic target. Prostaglandins Leukot. Essent. Fatty Acids, 2019, 140, 51-56.
[http://dx.doi.org/10.1016/j.plefa.2018.11.016]
[8]
Covey, D.P.; Mateo, Y.; Sulzer, D.; Cheer, J.F.; Lovinger, D.M. Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology, 2017, 124, 52-61.
[http://dx.doi.org/10.1016/j.neuropharm.2017.04.033]
[9]
Morales, P.; Reggio, P.H.; Jagerovic, N. An overview on medicinal chemistry of synthetic and natural derivatives of cannabidiol. Front. Pharmacol., 2017, 8, 422.
[http://dx.doi.org/10.3389/fphar.2017.00422]
[10]
Nadeem, S.; Sirajuddin, M.; Ahmad, S.; Tirmizi, S.A.; Ali, M.I.; Hameed, A. Synthesis, spectral characterization and in vitro antibacterial evaluation and Petra/Osiris/Molinspiration analyses of new Palladium(II) iodide complexes with thioamides. Alex. J. Med., 2016, 52(3), 279-288.
[http://dx.doi.org/10.1016/j.ajme.2015.10.003]
[11]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[12]
Isyaku, Y.; Uzairu, A.; Uba, S. Computational studies of a series of 2-substituted phenyl-2-oxo-, 2-hydroxyl- and 2-acylloxyethylsulfo namides as potent anti-fungal agents. Heliyon, 2020, 6(4), e03724.
[http://dx.doi.org/10.1016/j.heliyon.2020.e03724] [PMID: 32322718]
[13]
Guerra, L.R.; de Souza, A.M.T.; Côrtes, J.A.; Lione, V.O.F.; Castro, H.C.; Alves, G.G. Assessment of predictivity of volatile organic com-pounds carcinogenicity and mutagenicity by freeware in silicomodels. Regul. Toxicol. Pharmacol., 2017, 91, 1-8.
[http://dx.doi.org/10.1016/j.yrtph.2017.09.030] [PMID: 28970106]
[14]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and perme-ability in drug discovery and development settings. Adv. Drug Deliv. Rev., 1997, 23(1-3), 3-25.
[http://dx.doi.org/10.1016/S0169-409X(96)00423-1]
[15]
Poongavanam, V.; Doak, B.C.; Kihlberg, J. Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space. Curr. Opin. Chem. Biol., 2018, 44, 23-29.
[http://dx.doi.org/10.1016/j.cbpa.2018.05.010]
[16]
Daina, A.; Zoete, V. Application of the Swiss drug design online resources in virtual screening. Int. J. Mol. Sci., 2019, 20(18), 4612.
[http://dx.doi.org/10.3390/ijms20184612]
[17]
Ferreira, L.L.G.; Andricopulo, A.D. ADMET modeling approaches in drug discovery. Drug Discovery Today, 2019, 24(5), 1157-1165.
[http://dx.doi.org/10.1016/j.drudis.2019.03.015]
[18]
Chen, D.; Oezguen, N.; Urvil, P.; Ferguson, C.; Dann, S.M.; Savidge, T.C. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci. Adv., 2016, 2(3), e1501240.
[http://dx.doi.org/10.1126/sciadv.1501240] [PMID: 27051863]
[19]
Giordanetto, F.; Tyrchan, C.; Ulander, J. Intramolecular hydrogen bond expectations in medicinal chemistry. ACS Med. Chem. Lett., 2017, 8(2), 139-142.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00002]
[20]
Aungst, B.J. Optimizing oral bioavailability in drug discovery: An overview of design and testing strategies and formulation options. J. Pharm. Sci., 2017, 106(4), 921-929.
[http://dx.doi.org/10.1016/j.xphs.2016.12.002]
[21]
Aday, S.; Cecchelli, R.; Hallier-Vanuxeem, D.; Dehouck, M.P.; Ferreira, L. Stem cell-based human blood-brain barrier models for drug discovery and delivery. Trends Biotechnol., 2016, 34(5), 382-393.
[http://dx.doi.org/10.1016/j.tibtech.2016.01.001] [PMID: 26838094]
[22]
Warren, K.E. Beyond the blood: Brain barrier: The importance of central nervous system (CNS) pharmacokinetics for the treatment of CNS tumors, including diffuse intrinsic pontine glioma. Front. Oncol., 2018, 8, 239.
[http://dx.doi.org/10.3389/fonc.2018.00239]
[23]
Leite, C.F.; Almeida, T.R.; Lopes, C.S.; Dias da Silva, V.J. Multipotent stem cells of the heart-do they have therapeutic promise? In: Front. Physiol., 2015, 6, 00123.
[http://dx.doi.org/10.3389/fphar.2015.00123]
[24]
Roy, A.; Nair, S.; Sen, N.; Soni, N.; Madhusudhan, M.S. In silicomethods for design of biological therapeutics. Methods, 2017, 131, 33-65.
[http://dx.doi.org/10.1016/j.ymeth.2017.09.008]
[25]
Zoete, V.; Daina, A.; Bovigny, C.; Michielin, O. Swiss Similarity: A web tool for low to ultra high throughput ligand-based virtual screen-ing. J. Chem. Inf. Model., 2016, 56(8), 1399-1404.
[http://dx.doi.org/10.1021/acs.jcim.6b00174] [PMID: 27391578]
[26]
Mondello, E.; Quattrone, D.; Cardia, L.; Bova, G.; Mallamace, R.; Barbagallo, A.A.; Mondello, C.; Mannucci, C.; Di Pietro, M.; Arcoraci, V.; Calapai, G. Cannabinoids and spinal cord stimulation for the treatment of failed back surgery syndrome refractory pain. J. Pain Res., 2018, 11, 1761-1767.
[http://dx.doi.org/10.2147/JPR.S166617] [PMID: 30233233]
[27]
Di Marzo, V. New approaches and challenges to targeting the endocannabinoid system. Nat. Rev. Drug Discov., 2018, 17(9), 623-639.
[http://dx.doi.org/10.1038/nrd.2018.115] [PMID: 30116049]
[28]
Bow, E.W.; Rimoldi, J.M. The structure-function relationships of classical cannabinoids: CB1/CB2 modulation. Perspect. Med. Chem., 2016, 8, 17-39.
[http://dx.doi.org/10.4137/PMC.S32171] [PMID: 27398024]
[29]
Nevalainen, T. Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands. Curr. Med. Chem., 2014, 21(2), 187-203.
[http://dx.doi.org/10.2174/09298673113206660296] [PMID: 24164198]
[30]
Bihua, B.; Jiang, W.; Joseph, F.; Mohamed, N. An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Curr. Opin. Anaesthesiol., 2018, 31(4), 407-414.
[http://dx.doi.org/10.1097/ACO.0000000000000616]
[31]
Tham, M.; Yilmaz, O.; Alaverdashvili, M.; Kelly, M.E.M.; Denovan-Wright, E.M.; Laprairie, R.B. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br. J. Pharmacol., 2019, 176(10), 1455-1469.
[http://dx.doi.org/10.1111/bph.14440] [PMID: 29981240]
[32]
An, D.; Peigneur, S.; Hendrickx, L.A.; Tytgat, J. Targeting cannabinoid receptors: Current status and prospects of natural products. Int. J. Mol. Sci., 2020, 21(14), 5064.
[http://dx.doi.org/10.3390/ijms21145064] [PMID: 32709050]

Rights & Permissions Print Cite
Article Metrics
17
1
© 2024 Bentham Science Publishers | Privacy Policy