Your browser doesn't support javascript.
loading
Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.
Cloudsdale, Ian S; Dickson, John K; Barta, Thomas E; Grella, Brian S; Smith, Emilie D; Kulp, John L; Guarnieri, Frank; Kulp, John L.
Afiliação
  • Cloudsdale IS; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States. Electronic address: isclou@gmail.com.
  • Dickson JK; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States.
  • Barta TE; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States.
  • Grella BS; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States.
  • Smith ED; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States.
  • Kulp JL; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States; Conifer Point Pharmaceuticals, 3805 Old Easton Road, Doylestown, PA 18902, United States.
  • Guarnieri F; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States; Conifer Point Pharmaceuticals, 3805 Old Easton Road, Doylestown, PA 18902, United States.
  • Kulp JL; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States; Conifer Point Pharmaceuticals, 3805 Old Easton Road, Doylestown, PA 18902, United States. Electronic address: jlkjr@pobox.com.
Bioorg Med Chem ; 25(15): 3947-3963, 2017 08 01.
Article em En | MEDLINE | ID: mdl-28601508
We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s<100nM) with good oral bioavailability (F>20-58%).
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Renina / Inibidores Enzimáticos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Renina / Inibidores Enzimáticos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2017 Tipo de documento: Article