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Innovative Medicines & Omics SARS-CoV-2 inhibition by quinolines

negative interactions were noted between D187 and E166. for its involvement in hydration site interactions. Finally,
Furthermore, the Maestro (v13.6.122) 2D visualization negatively charged interactions were observed with E47
unveiled significant positively charged interactions with and E166.
R188 and polar interactions with residues H164, S144, The favorable interactions observed between the novel
and S46. The secondary amine outside the quinoline compounds and the majority of the subpockets (Figure 8)
nucleus can act as a hydrogen bond acceptor with H41 coupled with their replication of pharmacophoric
of the catalytic site. In contrast, the carbon atom between groups previously described in the literature suggest
the tertiary amine and the alkyne group at the end of the their potential efficacy in inhibiting SARS-CoV-2 M .
pro
molecule can act as a hydrogen bond donor to the residues Specifically, compound Q4b demonstrated a significant
of the adjacent subpockets.
3D arrangement within the catalytic site, effectively
Regarding compound Q2b (Figure 7E and F), it encompassing the additional subpockets. This finding
displayed hydrophobic interactions with C44 and C145 implies that the compound could exhibit enhanced
and a polar interaction with H41. Those hydrophobic effectiveness in subsequent experimental trials.
interactions occur through the quinoline nucleus and
the alkyne portion at the end of the chain. Furthermore, Comparing the docking of target compounds with the
it formed a negatively charged bond with E166, and the reference compounds, we can discern parallels within the
2D visualization revealed potential polar interactions with interactions occurring at the catalytic site residue and
H163, H164, B51, and T45, which also participated in a the ligand. For instance, molnupiravir (Figure 9A and B)
hydrogen bond. Residues T26, S144, and S46 were also displayed a hydrogen bond interaction with H41, C44,
indicated as potential polar interactions in addition to and C145, accompanied by polar interactions involving
the mentioned residues. The secondary carbon adjacent T45 and hydrophobic interactions with M49. In addition,
to the nitrogen of the quinoline nucleus can also act as a as elucidated by Maestro (v13.6.122), other interactions
hydrogen donor to the oxygen of the G166 residue. can also be discerned, including polar interactions
with H164, N142, S144, S46, T25, T190, and Q189, as
In the case of compound Q3a (Figure 7A and B), we well as hydrophobic interactions with M165 and L27.
observed hydrophobic interactions with A191, F140, and Furthermore, positively charged interactions with R188
M165. Moreover, polar bonds were formed with H41 and and negatively charged interactions with B187 were noted.
H172 and a hydrogen bond with F140. In addition, the
final amine portion can act as a hydrogen bond donor and In the case of mefloquine (Figure 9C and D), a hydrogen
perform salt bridge-type interactions with E166. The 2D bond interaction was established with H41. In contrast,
representation revealed potential hydrophobic interactions lopinavir, used as a positive control, exhibited hydrogen
pro
with M165, C145, and L141. Furthermore, negatively bond formation with M , specifically involving residues
charged interactions were identified between E166 and B187. H41, H163, and C145 (Figure 9E and F).
Compound Q3b (Figure 7G and H) displayed Mefloquine, a drug utilized for malaria treatment,
polar interactions with H41 and H163, as well as T45. has a partially understood mechanism, potentially acting
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Hydrophobic interactions were also observed with C44 on the ribosomes of Plasmodium falciparum. Although
and C145. In addition, a positively charged bond was it belongs to the aminoquinoline class proposed in this
formed with the R188 residue. Moreover, potential polar research, mefloquine serves as a negative control. This
interactions were revealed with Q189, N51, S46, and designation stems from its similar structural core that
S144, in addition to the mentioned residues. Hydrophobic lacks the requisite pharmacophoric groups for effective
pro
interactions were also identified with M165, F140, and M inhibition. Conversely, molnupiravir, a prodrug in
L141. In addition, the program suggested negatively the polymerase inhibitor class, interferes competitively
charged interactions with E166 and B187. with the viral RNA-dependent RNA polymerase (RdRp)
post-cellular uptake. 71,72 Despite suggestions of its efficacy
In conclusion, compound Q4b (Figure 7I and J)
exhibited polar interactions with H41 and H164, along with against COVID-19, its targeted action on a distinct viral
enzyme designates it as another negative control, as the
S46. Hydrophobic interactions were established with C44 study’s aim is to inhibit a viral protease.
and C145, as well as Y54. Finally, positively charged bonds
were formed with the R188 residue. Maestro unveiled Lopinavir, a protease inhibitor for human
potential polar interactions with Q189, N51, N142, T45, immunodeficiency virus (HIV) management, operates
T26, H163, and S144, apart from the mentioned residues. through competitive inhibition of viral protease, blocking
Notable hydrophobic interactions were identified with substrate cleavage and thus immature viral particle
M165 and L27. The G143 residue was also highlighted formation. Its effectiveness extends beyond HIV to other
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Volume 1 Issue 1 (2024) 100 doi: 10.36922/imo.3442