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1.
J Comput Aided Mol Des ; 26(10): 1143-57, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23053734

ABSTRACT

Drug design is a multi-parameter task present in the analysis of experimental data for synthesized compounds and in the prediction of new compounds with desired properties. This article describes the implementation of a binned scoring and composite ranking scheme for 11 experimental parameters that were identified as key drivers in the MC4R project. The composite ranking scheme was implemented in an AstraZeneca tool for analysis of project data, thereby providing an immediate re-ranking as new experimental data was added. The automated ranking also highlighted compounds overlooked by the project team. The successful implementation of a composite ranking on experimental data led to the development of an equivalent virtual score, which was based on Free-Wilson models of the parameters from the experimental ranking. The individual Free-Wilson models showed good to high predictive power with a correlation coefficient between 0.45 and 0.97 based on the external test set. The virtual ranking adds value to the selection of compounds for synthesis but error propagation must be controlled. The experimental ranking approach adds significant value, is parameter independent and can be tuned and applied to any drug discovery project.


Subject(s)
Drug Design , Receptor, Melanocortin, Type 4/agonists , Humans , Models, Biological , Quantitative Structure-Activity Relationship
2.
Bioorg Med Chem ; 12(5): 1151-75, 2004 Mar 01.
Article in English | MEDLINE | ID: mdl-14980627

ABSTRACT

A series of 3-mercapto-propionic acid derivatives that function as reversible inhibitors of carboxypeptidase U have been prepared. We present a successful design strategy using cyclic, low basicity guanidine mimetics resulting in potent, selective and bioavailable inhibitors of carboxypeptidase U (TAFIa).


Subject(s)
3-Mercaptopropionic Acid/chemical synthesis , Carboxypeptidase B2/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , 3-Mercaptopropionic Acid/pharmacology , Administration, Oral , Biological Availability , Drug Design , Enzyme Inhibitors/pharmacology , Guanidine , Humans , Inhibitory Concentration 50 , Molecular Mimicry , Structure-Activity Relationship
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