{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:47:49Z","timestamp":1791809269411,"version":"4.3.4"},"reference-count":57,"publisher":"American Chemical Society (ACS)","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/na","name":"Department of Science and Technology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["DST\/WISE-PDF\/LS-122\/2024"],"award-info":[{"award-number":["DST\/WISE-PDF\/LS-122\/2024"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) remains a major neurodegenerative disorder with limited therapeutic options, while currently approved acetylcholinesterase inhibitors (AChEIs), such as donepezil, are associated with adverse effects including cardiotoxicity. Here, we integrated a deep learning-based framework to design novel AChEIs candidates with improved predicted cardiac safety. A reinforcement learning-guided GraphVAE (RL-GraphVAE) was employed for target-biased molecular generation. The generated compounds were prioritized through CardiotoxPred-based cardiotoxicity screening, molecular docking, triplicate molecular dynamics simulations, and chemical synthesis. Experimental evaluation identified D0209 as a lead molecule exhibiting a noncompetitive inhibition mechanism. Notably, compared with donepezil, D0209 showed \u223c43-fold lower hERG channel inhibition, indicating an improved cardiac safety profile. Overall, this integrated computational and experimental workflow demonstrates the utility of generative modeling for the discovery of novel leads with improved predicted safety profiles, providing promising starting points for further optimization and biological evaluation.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c02233","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:02:14Z","timestamp":1790701334000},"page":"12723-12739","source":"Crossref","is-referenced-by-count":0,"title":["Generative AI-Assisted\nMolecular Design of AChEIs"],"prefix":"10.1021","volume":"66","author":[{"given":"Dhairiya","family":"Agarwal","sequence":"first","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research , , S. A. S. Nagar , ,","place":["Punjab, India, 160062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh Kumar","family":"Gautam","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology (BHU) , , , ,","place":["Varanasi, U.P., India, 221005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav","family":"Gupta","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research , , S. A. S. Nagar , ,","place":["Punjab, India, 160062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal","family":"Chaurasia","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology (BHU) , , , ,","place":["Varanasi, U.P., India, 221005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Sharma","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research , , S. A. S. Nagar , ,","place":["Punjab, India, 160062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanmaykumar","family":"Varma","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research , , S. A. S. Nagar , ,","place":["Punjab, India, 160062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8003-5566","authenticated-orcid":true,"given":"Gyan","family":"Modi","sequence":"additional","affiliation":[{"name":"Indian Institute of Technology (BHU) , , , ,","place":["Varanasi, U.P., India, 221005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1817-2172","authenticated-orcid":true,"given":"Sankar K.","family":"Guchhait","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research , , S. A. S. Nagar , ,","place":["Punjab, India, 160062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6922-4809","authenticated-orcid":true,"given":"Prabha","family":"Garg","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research , , S. A. S. Nagar , ,","place":["Punjab, India, 160062"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"2","key":"2026101208082517700_cit1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1017\/S1461145700001942","article-title":"The Cholinergic\nDeficit in Alzheimer\u2019s Disease: Impact on Cognition, Behaviour\nand Function","volume":"3","author":"Mega","year":"2000","journal-title":"International Journal of Neuropsychopharmacology"},{"key":"2026101208082517700_cit2","unstructured":"Global action plan on the public health response\nto dementia 2017\u20132025. https:\/\/www.who.int\/publications\/i\/item\/9789241513487 (accessed\n2025\u201307\u201314)."},{"key":"2026101208082517700_cit3","unstructured":"Dementia. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dementia (accessed\n2025\u201307\u201314)."},{"key":"2026101208082517700_cit4","unstructured":"Dementia facts and\nfigures | Alzheimer\u2019s Disease International\n(ADI). https:\/\/www.alzint.org\/about\/dementia-facts-figures\/ (accessed 2025\u201307\u201314)."},{"issue":"C","key":"2026101208082517700_cit5","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/0166-2236(82)90165-5","article-title":"The Cholinergic System in Alzheimer\u2019s Disease","volume":"5","author":"Perry","year":"1982","journal-title":"Trends Neurosci"},{"issue":"8000","key":"2026101208082517700_cit6","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1016\/S0140-6736(76)91936-X","article-title":"SELECTIVE LOSS\nOF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER\u2019S\nDISEASE","volume":"308","author":"Davies","year":"1976","journal-title":"Lancet"},{"issue":"2","key":"2026101208082517700_cit7","doi-asserted-by":"publisher","first-page":"615","DOI":"10.3233\/JAD-132690","article-title":"Efficacy and Safety\nof Donepezil, Galantamine, Rivastigmine, and\nMemantine for the Treatment of Alzheimer\u2019s Disease: A Systematic\nReview and Meta-Analysis","volume":"41","author":"Tan","year":"2014","journal-title":"Journal of Alzheimer\u2019s\nDisease"},{"key":"2026101208082517700_cit8","doi-asserted-by":"publisher","first-page":"3267","DOI":"10.2147\/DDDT.S86463","article-title":"A Fixed-Dose Combination of Memantine Extended-Release\nand Donepezil in the Treatment of Moderate-to-Severe Alzheimer\u2019s\nDisease","volume":"10","author":"Deardorff","year":"2016","journal-title":"Drug Des. 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Officinalis (Amla)\nas Natural BACE1 Inhibitors: An in-Silico Study","volume":"42","author":"Agarwal","year":"2024","journal-title":"J. Biomol. Struct. Dyn."},{"issue":"8","key":"2026101208082517700_cit44","doi-asserted-by":"publisher","first-page":"4069","DOI":"10.1063\/1.449071","article-title":"The Nose\u2013Hoover\nThermostat","volume":"83","author":"Evans","year":"1985","journal-title":"J. Chem. Phys."},{"issue":"3","key":"2026101208082517700_cit45","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical\nDynamics: Equilibrium Phase-Space Distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A (Coll. Park)."},{"issue":"5","key":"2026101208082517700_cit46","doi-asserted-by":"publisher","first-page":"3145","DOI":"10.1103\/PhysRevE.47.3145","article-title":"Constant-Temperature\nMolecular Dynamics\nwith Momentum Conservation","volume":"47","author":"Cho","year":"1993","journal-title":"Phys. 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Chem."},{"key":"2026101208082517700_cit51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112257","article-title":"Design, Synthesis and\nBiological Evaluation of Novel Naturally-Inspired Multifunctional\nMolecules for the Management of Alzheimer\u2019s Disease","volume":"198","author":"Singh","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"2026101208082517700_cit52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117831","article-title":"Design, Synthesis, and Biological\nEvaluation of Caffeic Acid-Based\nNovel Multifunctional Molecules for the Management of Alzheimer\u2019s\nDisease","volume":"296","author":"Kumar","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"2026101208082517700_cit53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.118047","article-title":"Novel Benzothiazole-Based\nCholinesterase Inhibitors with Amyloid Beta Disaggregation and Antioxidant\nActivity against Alzheimer\u2019s Disease","volume":"298","author":"Bhardwaj","year":"2025","journal-title":"Eur. J. Med. Chem."},{"issue":"2","key":"2026101208082517700_cit54","doi-asserted-by":"publisher","first-page":"219","DOI":"10.2174\/0118715249268585240107184956","article-title":"Lead Identification Through In Silico Studies: Targeting Acetylcholinesterase Enzyme\nAgainst Alzheimer\u2019s\nDisease","volume":"24","author":"Agarwal","year":"2024","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"2026101208082517700_cit55","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1145\/2939672.2939785","article-title":"XGBoost: A Scalable Tree Boosting System","author":"Chen","year":"2016","journal-title":"Proceedings of the ACM SIGKDD International Conference on\nKnowledge Discovery and Data Mining"},{"issue":"6","key":"2026101208082517700_cit56","doi-asserted-by":"publisher","first-page":"2584","DOI":"10.1021\/jm501535r","article-title":"CNS Drug Design:\nBalancing Physicochemical Properties for Optimal Brain Exposure","volume":"58","author":"Rankovic","year":"2015","journal-title":"J. Med. 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