Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach

Abstract

As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and M^pro main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with M^pro, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for M^pro and RdRp.

Keywords: COVID-19; Corona virus; Covalent docking; Main protease; Molecular dynamics simulations; Molecular modelling; Pyrimidine based remdesivir analogues; RNA-dependent DNA polymerase; SARS CoV-2.

Fig. 1

Interaction of M^pro with A) Ligand [3] BzV_0Ura and B) Ligand [5] EeV_0Tyr. The ligand is represented in ball and stick with green carbons. Pink dotted lines are the hydrogen bonds and the measures are the distances in Å. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

RMSD of the complexes A) M^pro-Ligand [3]-BzV_0Ura; B) M^pro-Ligand [5]-EeV_0Tyr; C and D) RMSF of the target upon binding of ligand3-BzV_0Ura and Ligand5-EeV_0Tyr, respectively. Green lines represent the residues which interacted with the ligand. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Interaction Plot for A) M^pro-Ligand [3]-BzV_0Ura; B) M^pro-Ligand [5]-EeV_0Tyr during Simulation.

Fig. 4

Interaction of M^pro with covdocked A) Ligand4-EeV_0Cys and B) Ligand5-EeV_0Tyr. The ligand is represented in ball and stick with cyan carbons. Pink dotted lines are the hydrogen bonds and the measures are the distances in Angstrom. Yellow bond inside the black dotted circle shows the covalent bond. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

2D Interaction plot of the covalent docked M^pro-ligand complexes. A) M^pro-Ligand 4, B) M^pro-Ligand 5.

Fig. 6

RMSD of the covalent bound complexes A) M^pro-Ligand4-EeV_0Cys B) M^pro-ligand5-EeV_0Tyr. C and D) RMSF of the target upon binding of ligand4-EeV_0Cys and ligand5-EeV_0Tyr, respectively. Green lines represent the residues which interacted with the ligand. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Radius of gyration and the solvent accessible surface area during the 150 ns Simulation time.

Fig. 8

Interaction of RdRp with A) Ligand1-BzV_0Cys; B) Ligand2-BzV_0Tyr. The ligand is represented in ball and stick with blue carbons. Pink dotted lines are the hydrogen bonds and the measures are the distances in Angstrom. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 9

RMSD of the complexes A) RdRp-ligand1-BzV_0Cys, B) RdRp-ligand2-BzV_0Tyr; (C and D) RMSF of the target upon binding of ligand1-BzV_0Cys and ligand2-BzV_0Tyr, respectively. Green lines represent the residues which interacted with the ligand. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 10

Interaction Plot for A) RdRp-ligand1-BzV_0Cys, B) RdRp-ligand2-BzV_0Tyr during Simulation.