Document Detail


Composite multi-parameter ranking of real and virtual compounds for design of MC4R agonists: Renaissance of the Free-Wilson methodology.
MedLine Citation:
PMID:  23053734     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Ingemar Nilsson; Magnus O Polla
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-2
Journal Detail:
Title:  Journal of computer-aided molecular design     Volume:  -     ISSN:  1573-4951     ISO Abbreviation:  J. Comput. Aided Mol. Des.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8710425     Medline TA:  J Comput Aided Mol Des     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
CVGI AstraZeneca R&D Mölndal, 431 83, Mölndal, Sweden, Ingemar.nilsson@astrazeneca.com.
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