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Author(s): Maykel Cruz-Monteagudo
M. Natália D. S. Cordeiro
Marta Teijeira
Maykel P. González
Fernanda Borges
Title: Multidimensional Drug Design: Simultaneous Analysis of Binding and Relative Efficacy Profiles of N6-substituted-4¢-thioadenosines A3 Adenosine Receptor Agonists
Issue Date: 2010
Abstract: Desirability theory (DT) is a well-known multi-criteriadecision-making approach. In this work, DTis employed as a prediction model (PM) interpretationtool to extract useful information on thedesired trade-offs between binding and relativeefficacy of N6-substituted-4¢-thioadenosines A3adenosine receptor (A3AR) agonists. At the sametime, it was shown the usefulness of a parallel butindependent approach providing a feedback onthe reliability of the combination of propertiespredicted as a unique desirability value. The applianceof belief theory allowed the quantification ofthe reliability of the predicted desirability of acompound according to two inverse and independentbut complementary prediction approaches.This information is proven to be useful as a rankingcriterion in a ligand-based virtual screeningstudy. The development of a linear PM of theA3AR agonists overall desirability allows findingsignificant clues based on simple moleculardescriptors. The model suggests a relevant role ofthe type of substituent on the N6 position of theadenine ring that in general contribute to reducethe flexibility and hydrophobicity of the lead compound. The mapping of the desirability functionderived of the PM offers specific informationsuch as the shape and optimal size of the N6 substituent.The model herein developed allows asimultaneous analysis of both binding and relativeefficacy profiles of A3AR agonists. The informationretrieved guides the theoretical design andassembling of a combinatorial library suitable forfiltering new N6-substituted-4¢-thioadenosinesA3AR agonist candidates with simultaneouslyimproved binding and relative efficacy profiles.The utility of the desirability ⁄ belief-based proposedvirtual screening strategy was deducedfrom our training set. Based on the overall results,it is possible to assert that the combined use ofdesirability and belief theories in computationalmedicinal chemistry research can aid the discoveryof A3AR agonist candidates with favorable balancebetween binding and relative efficacyprofiles.
Subject: Neuroquímica, Química aplicada, Engenharia química
Neurochemistry, Applied chemistry, Chemical engineering
Scientific areas: Ciências da engenharia e tecnologias::Engenharia química
Engineering and technology::Chemical engineering
Document Type: Artigo em Revista Científica Internacional
Rights: restrictedAccess
Appears in Collections:FCUP - Artigo em Revista Científica Internacional

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