Comparative docking studies to understand the binding affinity of nicotine with soluble ACE2 (sACE2)-SARS-CoV-2 complex over sACE2

Abstract

The study aimed to validate the proficiency of nicotine binding with the soluble angiotensin-converting enzyme II receptor (sACE2) with or without SARS-CoV-2 in the context of its binding affinity. Modelled human sACE2 and the spike (S1) protein of Indian SARS-CoV-2 (INS1) docked with each other. On the other hand, nicotine docked with sACE2 in the presence or absence of SARS-CoV-2. Nicotine established a stable interaction with negatively charged Asp368 of sACE2, which in turn binds with amino acids like Thr362, Lys363, Thr365, Thr371, and Ala372. In the presence of nicotine, INS1 and sACE2 showed a reduced binding affinity score of -12.6 kcal/mol (Vs -15.7 kcal/mol without nicotine), and a lowered interface area of 1933.6 Ų (Vs 2057.3Ų without nicotine). The neuronal nicotinic acetylcholine receptor (nN-AChR) and angiotensin-converting enzyme 2 (ACE2) receptor showed 19.85% sequence identity among themselves. Following these receptors possessed conserved Trp302 and Cys344 amino acids between them for nicotine binding. However, nicotine showed a higher binding affinity score of -6.33 kcal/mol for the sACE2-INS1 complex than the sACE2 alone with -5.24 kcal/mol. A lowered inhibitory constant value of 22.95μM recorded while nicotine interacted with the sACE2-INS1 complex over the sACE2 alone with 151.69 μM. In summary, nicotine showed a profound binding affinity for the sACE2-INS1 complex than the sACE2 alone paving for the clinical trials to validate its therapeutic efficacy as a bitter compound against the SARS-CoV-2 virulence.

Keywords: Neuronal nicotinic acetylcholine receptor; Nicotine; SARS-CoV-2; Smokers; Soluble ACE2; sACE2-INS1 complex.

Graphical abstract

Fig. 1

Nicotine docking with the soluble angiotensin-converting enzyme 2 (sACE2) receptor. Nicotine got bound into the active site of sACE2 located near to the SARS-CoV-2 binding site.

Fig. 2

Nicotine docking with the soluble angiotensin-converting enzyme 2 (sACE2) and sACE2-SARS-CoV-2 complex. (a) Nicotine bound intensely into the active site pocket of sACE2 by establishing stable interactions with Asp382, Tyr385, His378, Gly405 through His401 away from the SARS-CoV-2 binding site. (b) Nicotine bound more firmly into the active site pocket of sACE2-SARS-CoV-2 complex (mimicking the diseased condition) by establishing the stable interactions with the Ala372, Thr362, Lys363, Thr365, and Thr371 residues through Asp368 in proximal to the spike (S1) protein binding site of SARS-CoV-2.

Fig. 3

Nicotine binding (in black coloured stick structure) with the human neuronal alpha4-beta2 nicotine-acetylcholine receptor (in green coloured surface structure) with the key amino acid residues engaged in its interaction shown in the surface view.

Fig. 4

Pairwise sequence alignment profile of the soluble angiotensin-converting enzyme 2 (sACE2) with the neuronal nicotinic acetylcholine receptor (nN-AChR). Paired residues that are exclusively engaged in nicotine binding with the nN-AChR has been marked using the downward arrows on the profile template. The Trp302 and Cys344 of sACE2 residues are highly conserved in compliance to the Trp 156 and Cys 199 residues of nN-AChR. Also, the Trp349 residue of sACE2 and its alternative Tyr204 residue of nN-AChR shared similar characteristics in nature.

Fig. 5

(a)Structural binding characteristics of nicotine with the soluble angiotensin-converting enzyme 2 (sACE2) in compliance with its interaction with the neuronal nicotinic acetylcholine receptor (nN-AChR). Conserved residues such as Trp349, Cys344, and His345 of nN-AChR (highlighted in maroon colour) shares proximity with the sACE2 (highlighted in green colour). The conserved residues underlie the stable interaction of nicotine with the sACE2 residues through His401. Asp303 and Trp302 residues of nN-AChR are located far away from the nicotine binding site (highlighted using the maroon colour). (b): Structural binding characteristics of nicotine with the soluble angiotensin-converting enzyme 2 (sACE2)-SARS-CoV-2 complex in the context of its interaction with the neuronal nicotinic acetylcholine receptor (nN-AChR). Nicotine bound proximal to the conserved Cys344 residue (marked in maroon colour) of the sACE2-SARS-CoV-2 complex which in-turn facilitates its further interaction with the other flanking residues of sACE2 through Asp368 (marked in green colour).