Retro-forward synthesis design and experimental validation of potent structural analogs of known drugs

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dc.contributor.authorMakkawi, Ahmad
dc.contributor.authorBeker, Wiktor
dc.contributor.authorWołos, Agnieszka
dc.contributor.authorManna, Sabyasachi
dc.contributor.authorRoszak, Rafał
dc.contributor.authorSzymkuć, Sara
dc.contributor.authorMoskal, Martyna
dc.contributor.authorKoshevarnikov, Aleksei
dc.contributor.authorMolga, Karol
dc.contributor.authorŻądło-Dobrowolska, Anna
dc.contributor.authorGrzybowski, Bartosz A.
dc.contributor.organizationInstitute of Organic Chemistry, Polish Academy of Sciences
dc.contributor.organizationAllchemy, Inc., Highland, IN, USA
dc.contributor.organizationCenter for Algorithmic and Robotized Synthesis, Institute for Basic Science, Republic of Korea
dc.contributor.organizationDepartment of Chemistry, Ulsan Institute of Science and Technology, Republic of Korea
dc.date.accessioned2025-05-09T11:45:17Z
dc.date.available2025-05-09T11:45:17Z
dc.date.issued2025
dc.description.abstractGeneration of structural analogs to “parent” molecule(s) of interest remains one of the important elements of drug development. Ideally, such analogs should be synthesizable by concise and robust synthetic routes. The current work illustrates how this process can be facilitated by a computational pipeline spanning (i) diversification of the parent via bioisosteric replacements, (ii) retrosynthesis of the thus generated “replicas” to identify substrates, (iii) forward syntheses originating from these substrates (and synthetically versatile “auxiliaries”) and guided “towards” the parent, and (iv) evaluation of the candidates for target binding and other medicinal-chemical properties. This pipeline proposes syntheses to thousands of readily makeable analogs in a matter of minutes, and is deployed here to validate by experiment seven structural analogs of Ketoprofen and six analogs of Donepezil. The concise, computer-designed syntheses are confirmed in 12 out of 13 cases, offering access to several potent inhibitors. While the synthesis-design component is robust, binding affinities are predicted less accurately although still to the order-of-magnitude, which may be valuable in discerning promising from inadequate binders.en
dc.description.sponsorshipNational Science Center, Poland (grant Maestro, 2018/30/A/ST5/00529); National Science Centre, Poland (grant SONATA, 2020/39/D/ST4/01890); Basic Science, Korea (project code IBS-R020-D1)
dc.identifier.citationChem. Sci., 2025, Advance Article // https://doi.org/10.1039/D5SC00070J
dc.identifier.doi10.1039/D5SC00070J
dc.identifier.issn2041-6520
dc.identifier.issn2041-6539
dc.identifier.urihttps://open.icm.edu.pl/handle/123456789/25823
dc.language.isoen
dc.publisherRoyal Society of Chemistry
dc.rightsUznanie autorstwa-Użycie niekomercyjne 3.0 Unporteden
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/
dc.sourceChemical Science
dc.titleRetro-forward synthesis design and experimental validation of potent structural analogs of known drugsen
dc.typearticle
dc.type.versionpublishedVersion
person.identifier.orcidŻądło-Dobrowolska, Anna [0000-0003-4240-9851]
person.identifier.orcidGrzybowski, Bartosz A. [0000-0001-6613-4261]
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