Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis

Abstract

Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.

Keywords: SARS-CoV-2; main protease enzyme coronavirus; molecular dynamics simulation; noscapine conjugates.

Graphical abstract

Figure 1.

(A) Three-dimensional crystal structure of Mpro enzyme of coronavirus-19 and depiction of three major domains in the circles (B) Ramachandran plot assessment of Mpro enzyme, (C) Secondary structure analyses of Mpro protein (D) Local quality estimation of the 3 D structure of Mpro enzyme with native structures.

Figure 2.

Binding complexation of Mpro (ribbon view in sky blue color) with different conjugate ligands (A) Mpro-Noscpapine complex, noscapine in yellow color (B) Mpro-Nos-Hydroxychloroquine complex, Nos-Hcq conjugate in red color (C) Mpro-Nos-Chloroquine complex, Nos-Cq conjugate in coco color (D) Mpro-Nos-Favlplravir complex, Nos-Fav conjugate in blue color (E) Mpro-Nos-Umifenovir color, Nos-Umi conjugate in orange color (F) Mpro-Nos-Galidesivir complex, Nos-Gdr conjugate in black color.

Figure 3.

Noscapine-Antiviral conjugates to Mpro binding domain analysis, surface view of the binding groove of Mpro in sky blue color in Leftside, and conjugate binding pattern in domains in Rightside (A) Mpro-Nos-Hydroxychloroquine complex (B) Mpro-Nos-Chloroquine complex C) Mpro-Nos-Favlplravir complex (D) Mpro-Nos-Umifenovir complex (E) Mpro-Nos-Galidesivir complex.

Figure 4.

Noscapine conjugates Mpro binding molecular contacts analysis (A) Mpro-Nos-Chloroquine complex (B) Mpro-Nos-Favlplravir complex (C) Mpro-Nos-Hydroxychloroquine complex (D) Mpro-Nos-Umifenovir complex (E) Mpro-Nos-Galidesivir complex.

Figure 5.

Protein complex MD simulation analyses of Nos-Hcq conjugation (A) Root mean square deviation plot of Mpro receptor with Nos-Hcq conjugation, green color native Mpro protein, purple Mpro-NosHcq complex (B) Radius of gyration analysis of interacting complex of Mpro with Nos-Hcq conjugation, green color native Mpro protein, purple Mpro-NosHcq complex (C) Root mean square fluctuation plot of Mpro receptor with Nos-Hcq conjugation, green color native Mpro protein, purple Mpro-NosHcq complex (D) SASA analyses of Mpro receptor with Nos-Hcq conjugation, green color native Mpro protein, purple Mpro-NosHcq complex, (E) Secondary structure analysis of Mpro in the native state (F) Secondary structure analysis of Mpro with Nos-Hcq conjugation for throughout the 100 ns MD simulation.

Figure 6.

Mpro with Nos-Hcq conjugation binding energy analyses (A) GROMACS total energy analysis of complex system (B) Two-dimensional projection of simulated trajectory (C) Plot statistics showing the pressure variations of the system (D) Equilibrated temperature plot of stabilized system trajectory during the energy minimization (E) Graph depicting the density of complex system through the MD simulation (F) Hydrogen bond contributions to the complex system through the MD simulation, green color native Mpro protein, purple Mpro-NosHcq complex (G) Hydrogen bond statistics depicting the involvement of a large number of hydrogen bonds in the intermolecular binding of Mpro-NosHcq system.

Figure 7.

Principal component analyses for Mpro binding to ligand Nos-Hcq (A) PC1, (B) PC2, (C) PC3 based on MD trajectories from the internal mode atomic motions in correlation with protein dynamics secondary structures. The secondary structures schematics are added to the top and bottom (D) Superimposed ligand conformations to the receptor main protease protein of coronavirus (E) The dynamical residue cross-correlation map.

Figure 8.

Principal component analysis of clusters by protein complex dynamics from internal modes (A and B). PCA resulting trajectory frames change from blue to white to red conformation during the MD simulation run and recovered by changing conformations from black to red color. The trajectory snapshots are divided into two different clusters of the color black and red through the top three PC1, PC2, and PC3 spaces, (C and D) superimposed conformations of two clusters.

Figure 9.

Proposed schematic diagram for the chemical synthesis of Nos-Hcq conjugate.