In silico structure‐based design of GABA_B receptor agonists using a combination of docking and QSAR

Abstract

The study of γ‐aminobutyric acid B receptor (GABAB) activation is of great interest for several brain disorders. The search of new GABAB receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABAB 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 GABAB 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 GABAB receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABAB receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (ELUMO and T(N…O)) and the energy interaction with GABAB receptor (ETRP278). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the QLOO, QASYM, R02 and rm2 rules. Finally, six new compounds are proposed (35–40) with high potential to be used as GABAB receptor agonists.

The GABAB Receptor—Structure, Ligand Binding and Drug Development

“…These studies have not succeeded in obtaining clinical compounds, but with available 3D structures of the full receptor, new possibilities are provided also for new orthosteric compounds. Most of the in silico studies have been a combination of ligand based and structure based methods to identify potential hits and explore the VFT mechanisms [52,53,111,112].…”

Rational Drug Design of Axl Tyrosine Kinase Type I Inhibitors as Promising Candidates Against Cancer

“…They identified some key selective residues that might play an important role in the design of the novel ATP-competitive inhibitors (Zhu et al, 2019). Martínez-Campos et al (2019) in their work employed molecular docking: firstly the QSAR method to analyze all known gamma aminobutyric acid (GABA B ) receptor agonists and later a structure-based drug design strategy for the design of the novel compounds. They came up with six potent baclofen analogs targeted on the activation of the GABA B receptor (Martínez-Campos et al, 2019).…”

“…Martínez-Campos et al (2019) in their work employed molecular docking: firstly the QSAR method to analyze all known gamma aminobutyric acid (GABA B ) receptor agonists and later a structure-based drug design strategy for the design of the novel compounds. They came up with six potent baclofen analogs targeted on the activation of the GABA B receptor (Martínez-Campos et al, 2019). Liu et al (2019) used virtual screening, molecular docking, and molecular dynamics tools to identify the potential methylguanine-DNA methyltransferase (MGMT) inhibitors.…”

Respiratory rhythm generation and pattern formation: oscillators and network mechanisms

“…In order to develop a thorough understanding of the effect of GABA upon the brainstem neural respiratory circuitry, it will first prove prudent to discourse upon the structure and function of the fundamental biomolecular machinery mediating the described modulations (Martínez-Campos et al, 2019;Sadeghi et al, 2018). We shall have as our principal purpose to underscore and highlight the significance of the critical features of GABAAergic and GABABergic signaling as they contribute to generating and modulating the breathing rhythm and pattern (Bowery et al, 1990;Connors, 1992;Cramer et al, 2010;Gonzalez-Burgos, 2010;Kohl and Paulsen, 2010;Sil'kis, 1996).…”

“…The GABAA receptor represents an evolutionarily conserved heteropentameric receptor consisting of α-helices and β-pleated sheets with multiple ligand binding zones (Martínez-Campos et al, 2019). GABA ligand or synthetic agonist binding to the GABAA receptor generates immediate conformational changes of the receptor effecting the opening of an anion channel transmitting a selective chloride-based conductance ( Fig.…”