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In silico structure‐based design of GABA B receptor agonists using a combination of docking and QSAR
Author(s) -
MartínezCampos Zuleyma,
Pastor Nina,
PinedaUrbina Kayim,
GómezSandoval Zeferino,
FernándezZertuche Mario,
RazoHernández Rodrigo Said
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13580
Subject(s) - quantitative structure–activity relationship , agonist , docking (animal) , in silico , chemistry , receptor , stereochemistry , overfitting , inverse agonist , gabaa receptor , gabab receptor , computational biology , biochemistry , computer science , biology , artificial intelligence , medicine , artificial neural network , nursing , gene
The study of γ‐aminobutyric acid B receptor ( GABA B ) activation is of great interest for several brain disorders. The search of new GABA B receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABA B receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABA B receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABA B receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABA B receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features ( E LUMO and T(N…O)) and the energy interaction with GABA B receptor ( E TRP278 ). This model was validated by the QUIK , REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the Q LOO , Q ASYM , R 0 2 and r m 2 rules. Finally, six new compounds are proposed ( 35 – 40 ) with high potential to be used as GABA B receptor agonists.