Molecular modeling of potent novel sulfonamide derivatives as non-peptide small molecule anti-COVID 19 agents

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19. The Sulfonamides groups have been widely introduced in several drugs, especially for their antibacterial activities and generally prescribed for respiratory infections. On the other hand, imidazole groups have the multipotency to act as drugs, including antiviral activity. We have used a structure-based drug design approach to design some imidazole derivatives of sulfonamide, which can efficiently bind to the active site of SARS-CoV-2 main protease and thus may have the potential to inhibit its proteases activity. We conducted molecular docking and molecular dynamics simulation to observe the stability and flexibility of inhibitor complexes. We have checked ADMET (absorption, distribution, metabolism, excretion and toxicity) and drug-likeness rules to scrutinize toxicity and then designed the most potent compound based on computational chemistry. Our small predicted molecule non-peptide protease inhibitors could provide a useful model in the further search for novel compounds since it has many advantages over peptidic drugs, like lower side effects, toxicity and less chance of drug resistance. Further, we confirmed the stability of our inhibitor-complex and interaction profile through the Molecular dynamics simulation study. Our small predicted moleculeCommunicated by Ramaswamy H. Sarma.

Keywords: ADMET; MD simulation; SARS-CoV-2 main protease; drug-likeness; molecular docking; structure-based drug design.

Figure 1.

(a) Multiple sequence alignment results showing the similarity between four types of viruses and E.coli. (b) Superimposed Mpro structures of four viruses after multiple sequence alignment, the catalytic domain is highlighted by a box. SARS-CoV-2, SARS-CoV, Bat-CoV MERS-CoV are represented by light orange, green, red and pink, respectively.

Figure 2.

(2.1) Comprehensive perception of Mpro and M10 after docking. (a) The secondary structure of Mpro represented by cartoon and M10 represented is by ball and stick model and has been coloured according to elements. (b) The secondary structure of Mpro represented by hydrophobic surface and M10 represented is by stick model (c) Interactions of M10 with Mpro amino acids. Bonds are in dots. M10 surrounding amino acids are in three letters code represented in blue. (2.2) Comprehensive perception of SARS-CoV Mpro and M10 after docking. Figure legends are the same as Figure 2.1. (2.3) Comprehensive perception of BAT-CoVMpro and M10 after docking. Figure legends are the same as Fig. 2. (2.4) Comprehensive perception of MERS-COV Mpro and M10 after docking. Figure legends are the same as Figure 2.

Figure 2.

(2.1) Comprehensive perception of Mpro and M10 after docking. (a) The secondary structure of Mpro represented by cartoon and M10 represented is by ball and stick model and has been coloured according to elements. (b) The secondary structure of Mpro represented by hydrophobic surface and M10 represented is by stick model (c) Interactions of M10 with Mpro amino acids. Bonds are in dots. M10 surrounding amino acids are in three letters code represented in blue. (2.2) Comprehensive perception of SARS-CoV Mpro and M10 after docking. Figure legends are the same as Figure 2.1. (2.3) Comprehensive perception of BAT-CoVMpro and M10 after docking. Figure legends are the same as Fig. 2. (2.4) Comprehensive perception of MERS-COV Mpro and M10 after docking. Figure legends are the same as Figure 2.

Figure 2.

(2.1) Comprehensive perception of Mpro and M10 after docking. (a) The secondary structure of Mpro represented by cartoon and M10 represented is by ball and stick model and has been coloured according to elements. (b) The secondary structure of Mpro represented by hydrophobic surface and M10 represented is by stick model (c) Interactions of M10 with Mpro amino acids. Bonds are in dots. M10 surrounding amino acids are in three letters code represented in blue. (2.2) Comprehensive perception of SARS-CoV Mpro and M10 after docking. Figure legends are the same as Figure 2.1. (2.3) Comprehensive perception of BAT-CoVMpro and M10 after docking. Figure legends are the same as Fig. 2. (2.4) Comprehensive perception of MERS-COV Mpro and M10 after docking. Figure legends are the same as Figure 2.

Figure 2.

(2.1) Comprehensive perception of Mpro and M10 after docking. (a) The secondary structure of Mpro represented by cartoon and M10 represented is by ball and stick model and has been coloured according to elements. (b) The secondary structure of Mpro represented by hydrophobic surface and M10 represented is by stick model (c) Interactions of M10 with Mpro amino acids. Bonds are in dots. M10 surrounding amino acids are in three letters code represented in blue. (2.2) Comprehensive perception of SARS-CoV Mpro and M10 after docking. Figure legends are the same as Figure 2.1. (2.3) Comprehensive perception of BAT-CoVMpro and M10 after docking. Figure legends are the same as Fig. 2. (2.4) Comprehensive perception of MERS-COV Mpro and M10 after docking. Figure legends are the same as Figure 2.

Figure 3.

(a, b) The plots of HOMO and LUMO of M10. The positive electron density in pink and negative electron density in blue. (c, d) The plots of HOMO and LUMO of smx. The positive electron density in yellow and negative electron density in violet.

Figure 4.

Comparative MD simulation study of the docked complex of SARS-CoV-2 Mpro with smx and M10 compounds. RMSD of protein and ligand from the complex of (a) SARS-CoV-2 Mpro with smx and (b) SARS-CoV-2Mpro with M10 compound. (c) Number of H-bonds between SARS-CoV-2 Mpro with smx (red) and M10 (blue). (d) RMSF of SARS-CoV-2 Mproin the presence of smx (red) and M10 (blue).

Figure 5.

Effectiveness of M10 compound against other viruses SARS-CoV (PDB ID: 2VJ1), BAT-CoV (PDB ID: 4YOI) and MERS (PDB ID: 5WKL). (a) RMSD of protein and ligand from docked complex of SARS-CoV (left), BAT-CoV (middle) and MERS (right) with M10 compound. (b) Number of H-bonds between SARS-CoV (left), BAT-CoV (middle) and MERS (right) with M10.