Analysis of Differential Efficacy and Affinity of
GABA<sub>A</sub> (α1/α2) Selective Modulators
Qurrat
U. Ain
Robert M. Owen
Kiyoyuki Omoto
Rubben Torella
Krishna C. Bulusu
David C. Pryde
Robert C. Glen
Julian E. Fuchs
Andreas Bender
10.1021/acs.molpharmaceut.6b00813.s001
https://acs.figshare.com/articles/journal_contribution/Analysis_of_Differential_Efficacy_and_Affinity_of_GABA_sub_A_sub_1_2_Selective_Modulators/4043796
Selective
modulators of the γ-amino butyric acid (GABA<sub>A</sub>) family
of receptors have the potential to treat a range
of disease states related to cognition, pain, and anxiety. While the
development of various α subunit-selective modulators is currently
underway for the treatment of anxiety disorders, a mechanistic understanding
of the correlation between their bioactivity and efficacy, based on
ligand–target interactions, is currently still lacking. In
order to alleviate this situation, in the current study we have analyzed,
using ligand- and structure-based methods, a data set of 5440 GABA<sub>A</sub> modulators. The Spearman correlation (ρ) between binding
activity and efficacy of compounds was calculated to be 0.008 and
0.31 against the α1 and α2 subunits of GABA receptor,
respectively; in other words, the compounds had little diversity in
structure and bioactivity, but they differed significantly in efficacy.
Two compounds were selected as a case study for detailed interaction
analysis due to the small difference in their structures and affinities
(Δp<i>K</i><sub>i</sub><sub>(comp1_α1 – comp2_α1)</sub> = 0.45 log units, Δp<i>K</i><sub>i</sub><sub>(comp1_α2 – comp2_α2)</sub> =
0 log units) as compared to larger relative efficacies (ΔRE<sub>(comp1_α1 – comp2_α1)</sub> = 1.03, ΔRE<sub>(comp1_α2 – comp2_α2)</sub> = 0.21). Docking analysis
suggested that His-101 is involved in a characteristic interaction
of the α1 receptor with both compounds <b>1</b> and <b>2</b>. Residues such as Phe-77, Thr-142, Asn-60, and Arg-144 of
the γ chain of the α1γ2 complex also showed interactions
with heterocyclic rings of both compounds <b>1</b> and <b>2</b>, but these interactions were disturbed in the case of α2γ2
complex docking results. Binding pocket stability analysis based on
molecular dynamics identified three substitutions in the loop C region
of the α2 subunit, namely, G200E, I201T, and V202I, causing
a reduction in the flexibility of α2 compared to α1. These
amino acids in α2, as compared to α1, were also observed
to decrease the vibrational and dihedral entropy and to increase the
hydrogen bond content in α2 in the apo state. However, freezing
of both α1 and α2 was observed in the ligand-bound state,
with an increased number of internal hydrogen bonds and increased
entropy. Therefore, we hypothesize that the amino acid differences
in the loop C region of α2 are responsible for conformational
changes in the protein structure compared to α1, as well as
for the binding modes of compounds and hence their functional signaling.
2016-10-05 00:00:00
0 log units
201T
compounds 1
acid
Binding pocket stability analysis
α1
α2
Δ p K i
0.45 log units
GABA
202I
receptor
RE
200E
efficacy
interaction
hydrogen bond content
loop C region
α subunit-selective modulators