The γ-aminobutyric acid type A receptor (GABA (A) receptor) is a membrane protein activated by the neurotransmitter GABA. Structurally, this major inhibitory neurotransmitter receptor in the human central nervous system is a pentamer that can be built from a selection of 19 subunits consisting of α(1,2,3,4,5 or 6), β (1,2 or 3), γ (1,2 or 3), ρ (1,2 or 3), and δ, π, θ, and ε. This creates several possible pentameric arrangements, which also influence the pharmacological and physiological properties of the receptor. The complexity and heterogeneity of the receptors are further increased by the addition of short and long splice variants in several subunits and the existence of multiple allosteric binding sites and expansive ligands that can bind to the receptors. Therefore, a comprehensive understanding of the structure and function of the receptors is required to gain novel insights into the consequences of receptor dysfunction and subsequent drug development studies. Notably, advancements in computational-aided studies have facilitated the elucidation of residual interactions and exploring energy binding, which may otherwise be challenging to investigate. In this review, we aim to summarize the current understanding of the structure and function of GABA (A) receptors obtained from advancements in computational-aided applications.
Modulating cellular processes through extracellular chemical stimuli is medicinally an attractive approach to control disease conditions. GPCRs are the most important group of transmembranal receptors that produce different patterns of activations using intracellular mediators (such as G-proteins and Beta-arrestins). Adenosine receptors (ARs) belong to GPCR class and are divided into A1AR, A2AAR, A2BAR and A3AR. ARs control different physiological activities thus considered valuable target to control neural, heart, inflammatory and other metabolic disorders. Targeting ARs using small molecules essentially works by binding orthosteric and/or allosteric sites of the receptors. Although targeting orthosteric site is considered typical to modulate receptor activity, allosteric sites provide better subtype selectivity, saturable modulation of activity and variable activation patterns. Each receptor exists in dynamical equilibrium between conformational ensembles. The equilibrium is affected by receptor interaction with other molecules. Changing the population of conformational ensembles of the receptor is the method by which orthosteric, allosteric and other cellular components control receptor signaling. Herein, the interactions of ARs with orthosteric, allosteric ligands as well as intracellular mediators are described. A quinary interaction model for the receptor is proposed and energy wells for major conformational ensembles are retrieved.
A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.
Dengue is a potentially deadly disease with no effective drug. An in silico molecular docking was performed using Autodock
4.2.6 to investigate the molecular interactions between protease inhibitors, comprising antibiotic derivatives namely
doxycycline (3), rolitetracycline (5) and a non-steroidal anti-inflammatory drug (NSAID), meclofenamic acid (4), against
the NS2B-NS3 protease from dengue virus-2 (DENV-2). The non-competitive inhibitor (3) showed lower binding energy
(-5.15 kcal/mol) than the predicted competitive inhibitors 4 and 5 (-3.64 and -3.21 kcal/mol, respectively). Structural
analyses showed compound 3 that bound to a specific allosteric site, interacted with Lys74, a significant amino acid
residue bonded to one of the catalytic triad, Asp75. Compounds 4 and 5 showed direct binding with two of the catalytic
triad, His51 and Ser135, hence, predicted to be competitive inhibitors.
The allosteric pocket of the Dengue virus (DENV2) NS2B/NS3 protease, which is proximal to its catalytic triad, represents a promising drug target (Othman et al., 2008). We have explored this binding site through large-scale virtual screening and molecular dynamics simulations followed by calculations of binding free energy. We propose two mechanisms for enzyme inhibition. A ligand may either destabilize electronic density or create steric effects relating to the catalytic triad residues NS3-HIS51, NS3-ASP75, and NS3-SER135. A ligand may also disrupt movement of the C-terminal of NS2B required for inter-conversion between the "open" and "closed" conformations. We found that chalcone and adenosine derivatives had the top potential for drug discovery hits, acting through both inhibitory mechanisms. Studying the molecular mechanisms of these compounds might be helpful in further investigations of the allosteric pocket and its potential for drug discovery.