Evaluation of Inhibitory Activity In Silico of In-House Thiomorpholine Compounds between the ACE2 Receptor and S1 Subunit of SARS-CoV-2 Spike

Abstract

At the end of 2019, the world was struck by the COVID-19 pandemic, which resulted in dire repercussions of unimaginable proportions. From the beginning, the international scientific community employed several strategies to tackle the spread of this disease. Most notably, these consisted of the development of a COVID-19 vaccine and the discovery of antiviral agents through the repositioning of already known drugs with methods such as de novo design. Previously, methylthiomorphic compounds, designed by our group as antihypertensive agents, have been shown to display an affinity with the ACE2 (angiotensin converting enzyme) receptor, a key mechanism required for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) entry into target cells. Therefore, the objective of this work consists of evaluating, in silico, the inhibitory activity of these compounds between the ACE2 receptor and the S1 subunit of the SARS-CoV-2 spike protein. Supported by the advances of different research groups on the structure of the coronavirus spike and the interaction of the latter with its receptor, ACE2, we carried out a computational study that examined the effect of in-house designed compounds on the inhibition of said interaction. Our results indicate that the polyphenol LQM322 is one of the candidates that should be considered as a possible anti-COVID-19 agent.

Keywords: SARS-CoV-2; antivirals; spike; thiomorpholine derivatives.

Figure 1

RMSD (root-mean-square deviation) of each component of the system, in yellow boxes, chain 1 and 4 belonging to ACE2 are compared with a 0.46 Å deviation, and for the green boxes, chains 3 and 5 belonging to the spike are compared with a 0.47 Å deviation.

Figure 2

RMSD calculated from studied complexes ACE2–LQM304, ACE2–LQM318, ACE2–LQM319, ACE2–LQM322, and ACE2–LQM324.

Figure 3

RMSF of the studied complexes of each amino acid on ACE2 during ACE2–inhibitor simulations.

Figure 4

Hydrogen bonds of the ACE2–LQM322 system studied through the time of the dynamics.

Figure 5

Distance between ASN63 and ASN121 of ACE2–LQM304 (left) and ACE2–LQM322 (right) systems.

Figure 6

Hydrogen bonds present between the LQM304 (left) and LQM322 (right) compounds and ACE2 during molecular dynamics simulation.

Figure 7

RMSD of the reference ACE2–spike complex during the 40 ns simulation.

Figure 8

Hydrogen bonds present between ACE2 and the spike in the 45 ns simulation.

Figure 9

Hydrogen bonds present between ACE2–LQM322 and the spike in the 45 ns simulation.

Figure 10

Hydrogen bonds present between ACE2–LQM compounds and the spike in the 45 ns simulation.

Figure 10

Hydrogen bonds present between ACE2–LQM compounds and the spike in the 45 ns simulation.

Figure 11

RMSF for the ACE2 protein during simulations in complex with subunit S1.

Figure 12

RMSF for subunit S1 during simulations in complex with ACE2; the red shade corresponds to the RBD from subunit S1.

Figure 13

The patch analysis of the ACE2 (right) in absence and presence of LQM322: (left).

Figure 14

Complex of subunit S1 of the viral spike with the ACE2, with the representation of the viral RBD (receptor binding domain; red) and the ACE2 receptor amino acids involved (green).

Figure 15

Spike ACE2 system. Sphere model (coarse grain). ACE2 is depicted in brown.