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We present LigandForge, a webserver for structure-guided de novo ligand generation. LigandForge integrates structural validation and binding-site characterization; voxel-based property grid construction for spatial mapping of electrostatics and hydrophobicity; chemistry-aware fragment assembly; multi-objective lead optimization; and retrosynthetic feasibility analysis. The platform utilizes a structure-guided framework to assemble molecules from curated fragment libraries while enforcing physicochemical constraints, including molecular weight, LogP, and hybridization states. Generated molecules are refined via reinforcement learning and genetic algorithms which are subsequently evaluated using composite metrics such as the quantitative estimate of drug-likeness. By leveraging RDKit for cheminformatics and NGL viewer for real-time 3D visualization, LigandForge provides a synthesis-aware environment that bridges the gap between macromolecular structural data and experimentally feasible lead compounds without requiring local software installation.<\/jats:p>","DOI":"10.64898\/2026.03.31.715741","type":"posted-content","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T20:25:14Z","timestamp":1775247914000},"source":"Crossref","is-referenced-by-count":0,"title":["LigandForge: A Web Server for Structure-Guided De Novo Drug Design"],"prefix":"10.64898","author":[{"given":"Hossam","family":"Nada","sequence":"first","affiliation":[{"name":"Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Levente","family":"Sipos-Szab\u00f3","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group and Drug Innovation Centre, HUN-REN Research Centre for Natural Sciences, Magyar tud\u00f3sok krt. 2, 1117 Budapest, Hungary"},{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3., H-1111 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D\u00e1vid","family":"Bajusz","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group and Drug Innovation Centre, HUN-REN Research Centre for Natural Sciences, Magyar tud\u00f3sok krt. 2, 1117 Budapest, Hungary"},{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3., H-1111 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gy\u00f6rgy M.","family":"Keser\u0171","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Research Group and Drug Innovation Centre, HUN-REN Research Centre for Natural Sciences, Magyar tud\u00f3sok krt. 2, 1117 Budapest, Hungary"},{"name":"Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, M\u0171egyetem rkp. 3., H-1111 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moustafa","family":"Gabr","sequence":"additional","affiliation":[{"name":"Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040609550772000_2026.03.31.715741v1.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008178"},{"key":"2026040609550772000_2026.03.31.715741v1.2","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.5c00861"},{"key":"2026040609550772000_2026.03.31.715741v1.3","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2026.2623154"},{"key":"2026040609550772000_2026.03.31.715741v1.4","doi-asserted-by":"publisher","DOI":"10.1039\/D5CS00415B"},{"key":"2026040609550772000_2026.03.31.715741v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp163"},{"key":"2026040609550772000_2026.03.31.715741v1.6","doi-asserted-by":"crossref","unstructured":"Deng, D. in 2020 7th International Forum on Electrical Engineering and Automation (IFEEA). 949\u2013953.","DOI":"10.1109\/IFEEA51475.2020.00199"},{"key":"2026040609550772000_2026.03.31.715741v1.7","doi-asserted-by":"crossref","unstructured":"Khan, K. , Rehman, S. 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