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Between Theory and Practice: Computational/Experimental Integrated Approaches to Understand the Solubility and Lipophilicity of PROTACs.
Venturi, Andrea; Di Bona, Stefano; Desantis, Jenny; Eleuteri, Michela; Bartalucci, Matteo; Baroni, Massimo; Benedetti, Paolo; Goracci, Laura; Cruciani, Gabriele.
Afiliación
  • Venturi A; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
  • Di Bona S; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
  • Desantis J; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
  • Eleuteri M; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
  • Bartalucci M; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
  • Baroni M; Kinetic Business Centre, Molecular Discovery Ltd., Elstree, Borehamwood, Hertfordshire WD6 4PJ, United Kingdom.
  • Benedetti P; Kinetic Business Centre, Molecular Discovery Ltd., Elstree, Borehamwood, Hertfordshire WD6 4PJ, United Kingdom.
  • Goracci L; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
  • Cruciani G; Department of Chemistry, Biology and Biotechnology, University of Perugia, Via dell' Elce di Sotto 8, Perugia 06123, Italy.
J Med Chem ; 67(18): 16355-16380, 2024 Sep 26.
Article en En | MEDLINE | ID: mdl-39271471
ABSTRACT
Emerging drug candidates more often fall in the beyond-rule-of-five chemical space. Among them, proteolysis targeting chimeras (PROTACs) have gained great attention in the past decade. Although physicochemical properties of small molecules accomplishing Lipinski's rule-of-five can now be easily predicted through models generated by large data collections, for PROTACs the knowledge is still limited and heterogeneous, hampering their prediction. Here, the kinetic solubility and the coefficient of distribution at pH 7.4 (LogD7.4) of 44 PROTACs, designed and synthesized to cover a wide chemical space, were measured. Their generally low solubility and high lipophilicity required an optimization of the experimental methods. Concerning the LogD7.4, several in silico prediction tools were tested, which were quite accurate for classical small molecules but provided dissimilar outcomes for PROTACs. Finally, in silico models for the prediction of PROTACs' kinetic solubility and LogD7.4 were proposed by combining in-house generated experimental data with 3D description of PROTACs' structures.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Solubilidad / Proteolisis Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Solubilidad / Proteolisis Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos