In silico Modeling of α1A-Adrenoceptor: Interaction of its Normal and Mutated Active Sites with Noradrenaline as well as its Agonist and Antagonist

Abstract

Noradrenaline, like most other neurotransmitters, acts through various adrenoceptor subtypes. The structure and active site of adrenoceptors for the binding of noradrenaline were unknown, however, such information are crucial for understanding the molecular mechanism of action of neurotransmitters, including noradrenaline, in health and disease as well as for drug designing. In this in silico study, we modeled the 1A-adrenoceptor; a G protein coupled receptor and defined its active site. Further, molecular docking and interaction of noradrenaline and its agonist as well as antagonist with the so defined active site of the receptor was studied before and after in silico site directed mutation of several amino acid residues forming the active site. Our results indicate that the ARG166 is the most crucial residue for binding of noradrenaline and methoxamine to 1A-adrenoceptor and ILE178 is the most important residue for binding of prazosin to it. Thus, the observations provide new insights into the structure function relationship of 1A-adrenoceptor. A significant finding of this study is that the same residue of the active site may not be necessary for binding of a receptor with its natural ligand and its pharmacologically active known agonist and antagonist.

Structure-based inhibitor screening of natural products against NSP15 of SARS-CoV-2 revealed thymopentin and oleuropein as potent inhibitors

“…Docking studies [30][31][32][33][34] were performed using GOLD [35], and the protein was kept as a rigid molecule, and the number of Genetic Algorithm (GA) runs was set to 10 runs per ligand with the default search algorithm parameters. GOLD score was then used as the final scoring method.…”

“…Experimental studies on NSP15 have revealed that His-235, His-250, and Lys-290 (Ricagno et al 2006) are the critical residues for catalysis that are located in the C-terminal domain of the enzyme. Docking studies were performed using GOLD (Jones et al 1997), and the protein was kept as a rigid molecule, and the number of Genetic Algorithm (GA) runs was set to 10 runs per ligand with the default search algorithm parameters similar to our earlier reports (Vijayan and Mallick 2007;Eniyan et al 2018;Chadha et al 2018; Vijayan and Manohayan 2015; Mahendran and Vijayan 2018). GOLD score was then used as the final scoring method.…”

In Silico Analysis of Conformational Changes Induced by Normal and Mutation of Macrophage Infectivity Potentiator Catalytic Residues and its Interactions with Rapamycin

“…Therefore, we created an in silico mutagenesis [15,16] model for both important catalytic residues and validated the stability of the mutated model. Further, we have docked the known inhibitor rapamycin with native and mutants of Legionella Mip to analyze the binding affinity.…”

Discovery of Marine Sponge Compound as Promising Inhibitor for Macrophage Infectivity Potentiator (Mip) Protein against Chlamydia pneumoniae

“…Our goal is to design new marine drugs to treat the Chlamydial infections, as the lack of 3-dimensional structure available for Chlamydia pneumoniae Mip has been available. In order to help shed light on the complex mechanism of intracellular infection by these pathogens, homology modeling, pharmacophore model development and virtual screening studies were carried out based on drug design approach [12], [13] for the identification of new potential Mip inhibitors.…”