{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T09:06:20Z","timestamp":1779872780135,"version":"3.53.1"},"update-to":[{"DOI":"10.12688\/f1000research.171433.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000}},{"DOI":"10.12688\/f1000research.171433.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000}}],"reference-count":53,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"not applicable"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    Background The cannabinoid 1 (CB1) receptor is the primary target of \u0394\n                    <ns3:sup>9<\/ns3:sup>\n                    -tetrahydrocannabinol (\u0394\n                    <ns3:sup>9<\/ns3:sup>\n                    -THC), the psychoactive component of cannabis sativa (commonly known as \u201ckif\u201d in Morocco). Methods Here, we identified novel CB1 agonists using virtual screening approaches. First, we developed a pharmacophore model based on the known CB1 agonist AM11542 and screened a database of over three million compounds. Molecular docking using AutoDock Vina identified 61 hits with binding affinities of less than -9.00 Kcal\/mol. Subsequent ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) analysis narrowed the selection to 18 promising candidates. Results Among these, three agonists exhibited strong characteristics, including a favorable inhibition constant (Ki) and key hydrogen-bond interactions with critical residues in the CB1 binding pocket: PUBChem157251136 (Ki=2.09 nM), ZINC64438485 (Ki= 0.262 nM) and ZINC64438506 (Ki =0.244 nM). These agonists formed stable hydrogen bonds with CB1 binding pocket residues (Ser383, Ser173, His178 and Thr197). Molecular dynamics simulations (100 ns, GROMACS) demonstrated structural stability (RMSD &lt; 1 nm) and low conformational flexibility (RMSF &lt; 1 nm) for all complexes. MM-GBSA binding free energy calculations further confirmed the thermodynamic stability of all complexes, with interaction energies ranging from -30.59 to -49.98 kcal\/mol. These comprehensive simulations confirm that all identified agonist complexes maintain stable binding conformations with optimal interaction profiles characteristic of CB1 receptor activation. Conclusion These results could pave the way for researching and developing new quinazolinz-2, 4(1H, 3H)-Dione derivatives as a new class of CB1 receptor agonists.\n                  <\/ns3:p>","DOI":"10.12688\/f1000research.171433.3","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T08:34:11Z","timestamp":1779870851000},"page":"1322","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Quinazoline-2,4(1H,3H)-dione derivatives as new class of CB1 Agonists: A pharmacophore-based virtual screening workflow and drug discovery"],"prefix":"10.12688","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6909-9828","authenticated-orcid":false,"given":"Abdellah","family":"EL AISSOUQ","sequence":"first","affiliation":[{"name":"Fes Fes-Boulemane Universite Sidi Mohamed Ben Abdellah Faculte des Sciences et Techniques de Fes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MOURAD","family":"STITOU","sequence":"additional","affiliation":[{"name":"Fes Fes-Boulemane Universite Sidi Mohamed Ben Abdellah Faculte des Sciences et Techniques de Fes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Enneiymy","sequence":"additional","affiliation":[{"name":"Agadir Souss-Massa-Draa Universite Ibn Zohr Faculte des Sciences Agadir"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said","family":"El Rhabori","sequence":"additional","affiliation":[{"name":"Fes Fes-Boulemane Universite Sidi Mohamed Ben Abdellah Faculte des Sciences et Techniques de Fes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hicham","family":"Zaitan","sequence":"additional","affiliation":[{"name":"Fes Fes-Boulemane Universite Sidi Mohamed Ben Abdellah Faculte des Sciences et Techniques de Fes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelkrim","family":"Ouammou","sequence":"additional","affiliation":[{"name":"Fes Fes-Boulemane Universite Sidi Mohamed Ben Abdellah Faculte des Sciences Dhar El Mahraz-Fes"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fouad","family":"Khalil","sequence":"additional","affiliation":[{"name":"Fes Fes-Boulemane Universite Sidi Mohamed Ben Abdellah Faculte des Sciences et Techniques de Fes"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"89-97","DOI":"10.1006\/bbrc.1995.2437","article-title":"2-arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain.","volume":"215","author":"T Sugiura","year":"1995","journal-title":"Biochem. 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Overall, the manuscript is promising; however, I believe that&nbsp;\n<b>minor revisions<\/b>&nbsp;are required to improve clarity and scientific rigor. Please find below my main remarks for the authors: 1. The current title would benefit from being reformulated to make it more concise and more attractive to readers. A clearer title highlighting the novelty and the integrated workflow is recommended. \n<b>Response to Q1:<\/b> the title has been changed to \u201cQuinazoline-2,4(1H,3H)-dione derivatives as new class of CB1 Agonists: A pharmacophore-based virtual screening workflow and drug discovery\u201d  2. The authors mention the use of molecular dynamics (MD) simulations in the Materials and Methods section, but MD is not mentioned in the Abstract. For coherence and completeness, this important component of the workflow should be briefly stated in the Abstract.  \n<b>Response to Q2:&nbsp;<\/b>The molecular dynamics (MD) simulations are mentioned in the abstract, as shown in the following excerpt from the abstract section \u201cMolecular dynamics simulations (100 ns, GROMACS) demonstrated structural stability (RMSD &lt; 1 nm) and low conformational flexibility (RMSF &lt; 1 nm) for all complexes. MM-GBSA binding free energy calculations further confirmed the thermodynamic stability of all complexes, with interaction energies ranging from -30.59 to -49.98 kcal\/mol.  3.&nbsp;In the graphical abstract, the authors indicate two docking steps (first using AutoDock Vina, then AutoD ock4).It would be helpful to briefly clarify the rationale behind this double-docking strategy and how each tool contributes to the screening workflow.  \n<b>Response to Q3:<\/b>&nbsp;We thank the reviewer for raising this important point regarding our docking strategy. The double-docking approach was implemented to enhance the robustness and reliability of our virtual screening workflow.  4.&nbsp;The authors are encouraged to integrate a comparative discussion between the pharmacophore hits, docking scores, and the stability of key amino acids involved in ligand recognition, supported by MD fluctuation analysis (e.g., RMSF). This would reinforce the consistency and predictive power of the multi-step in silico approach.  5. Since none of the proposed candidates were synthesized or experimentally validated, the authors should clearly state the value of the in silico-only approach and discuss its limitations. It is also recommended to suggest potential collaboration with experimental researchers for future synthesis and biological evaluation.  6.&nbsp;Given that the identified compounds appear to be promising drug candidates, it would be appropriate to add a short section in the conclusion outlining perspectives for future work.  \n<b>Response to Q4, 4 and 6<\/b>&nbsp;: The identified compounds are promising drug candidates","URL":"https:\/\/f1000research.com\/articles\/14-1322\/v3#referee-comment-15172","order":1,"name":"referee-comment-15172","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.189041.r439371, Mourad Fawzi, Faculty of Sciences Semlalia, Cadi Ayyad University, Department of Chemistry, Laboratory of Molecular Chemistry, Marrakech, 30 Dec 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-1322\/v1#referee-response-439371","order":2,"name":"referee-response-439371","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>ABDELLAH EL AISSOUQ<\/b>; \n<i>Posted: 01 Jan 2026<\/i>; \n<b>Reviewer #2: <\/b> The study entitled &quot;Quinazoline-2,4(1H,3H)-dione derivatives as new class of CB1 Agonists: A pharmacophore-based virtual screening workflow and drug discovery&quot; presents a pharmacophore-based virtual screening of a large database aimed at developing new CB1 agonists. I believe this work is suitable for publication in&nbsp;F1000 Research&nbsp;before the minor revisions below: Comments for the authors:  Page 17: &quot;form two, two and three hydrogen bonds with the CB1 binding site, respectively, \u2026&quot; \u2013 The word &quot;two&quot; is repeated; please remove one. Some abbreviations are not clearly defined in the manuscript, such as&nbsp;GPCR&nbsp;and&nbsp;ICL3. Please ensure all abbreviations are spelled out upon first use. Page 19: The sentence \u030bTranslated with DeepL.com (free version)\u030b should be removed. More details about the advantage of work in conclusion are required Grammatical errors and typos&nbsp;are present throughout the manuscript. A thorough proofreading is recommended to improve clarity and language quality. Regarding&nbsp;Table 6: The reported&nbsp;K\u1d62&nbsp;values indicate that the screened compounds exhibit promising drug-like properties. Therefore, I suggest modifying the title to better reflect this finding. Proposed revision:  \n<b>Response to Questions 1-6:<\/b> We thank the reviewer for their insightful comments. All remarks have been addressed in the revised manuscript.&quot;","URL":"https:\/\/f1000research.com\/articles\/14-1322\/v3#referee-comment-15173","order":3,"name":"referee-comment-15173","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.197019.r466648, Samir Chtita, Bouchra Rossafi, Hassan II University of Casablanca, Morocco, 19 Mar 2026, version 3, indexed","URL":"https:\/\/f1000research.com\/articles\/14-1322\/v3#referee-response-466648","order":4,"name":"referee-response-466648","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}