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. 2021 Aug;39(12):4522-4535.
doi: 10.1080/07391102.2020.1779130. Epub 2020 Jun 18.

Identification of a novel dual-target scaffold for 3CLpro and RdRp proteins of SARS-CoV-2 using 3D-similarity search, molecular docking, molecular dynamics and ADMET evaluation

Adnane Aouidate  1 , Adib Ghaleb  2 , Samir Chtita  3 , Mohammed Aarjane  4 , Abdellah Ousaa  1 , Hamid Maghat  1 , Abdelouahid Sbai  1 , M'barek Choukrad  1 , Mohammed Bouachrine  1   5 , Tahar Lakhlifi  1
Affiliations

Identification of a novel dual-target scaffold for 3CLpro and RdRp proteins of SARS-CoV-2 using 3D-similarity search, molecular docking, molecular dynamics and ADMET evaluation

Adnane Aouidate et al. J Biomol Struct Dyn. 2021 Aug.

Abstract

The new SARS-CoV-2 coronavirus is the causative agent of the COVID-19 pandemic outbreak that affected whole the world with more than 6 million confirmed cases and over 370,000 deaths. At present, there are no effective treatments or vaccine for this disease, which constitutes a serious global health crisis. As the pandemic still spreading around the globe, it is of interest to use computational methods to identify potential inhibitors for the virus. The crystallographic structures of 3CLpro (PDB: 6LU7) and RdRp (PDB 6ML7) were used in virtual screening of 50000 chemical compounds obtained from the CAS Antiviral COVID19 database using 3D-similarity search and standard molecular docking followed by ranking and selection of compounds based on their binding affinity, computational techniques for the sake of details on the binding interactions, absorption, distribution, metabolism, excretion, and toxicity prediction; we report three 4-(morpholin-4-yl)-1,3,5-triazin-2-amine derivatives; two compounds (2001083-68-5 and 2001083-69-6) with optimal binding features to the active site of the main protease and one compound (833463-19-7) with optimal binding features to the active site of the polymerase for further consideration to fight COVID-19. The structural stability and dynamics of lead compounds at the active site of 3CLpro and RdRp were examined using molecular dynamics (MD) simulation. Essential dynamics demonstrated that the three complexes remain stable during simulation of 20 ns, which may be suitable candidates for further experimental analysis. As the identified leads share the same scaffold, they may serve as promising leads in the development of dual 3CLpro and RdRp inhibitors against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Keywords: 2019-Novel Coronavirus; COVID-19; main protease; molecular docking; molecular dynamics; polymerase.

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Figures

Figure 1.
Figure 1.
a) 3D-pharmacophores generated from Remdesivir and N3 inhibitors for RNA and 3CLpro respectively. With Green: Aromatic and lipophilic features, Magenta: Hydrogen bond acceptor features, Cyan: Hydrogen bond donor features, Orchid: Hydrogen bond donor and acceptor features.
Figure 2.
Figure 2.
3D-Binding modes of the six selected candidates in the substrate-binding site of 3CLpro, (A) 2001083-69-6 (−9,064 Kcal/mol), (B) 2001083-68-5 (−8.879 Kcal/mol), (C) 63248-75-9 (−8.857 Kcal/mol), (D) 264621-13-8 (−8.564 Kcal/mol),(E) 1025098-90-1 (−8.558 Kcal/mol) and (F) 1253912-09-2 (−8.400 Kcal/mol). The catalytic dyad Cys145-His41 is colored in yellow and green, respectively.
Figure 3.
Figure 3.
(a) & (b) shows the interaction of top hit molecules Dataset 2001083-69-6 and 2001083-68-5 with main protease of coronavirus for COVID-19.
Figure 4.
Figure 4.
3D-Binding modes of the six hits compounds in the substrate-binding site of RdRp, (A) 833463-10-86 (−9.529 Kcal/mol), (B) 833463-11-9 (−9.205 Kcal/mol), (C) 833465-33-1 (−9.162 Kcal/mol), (D) 178477-46-8 (−8.895 Kcal/mol),(E) 2001083-69-6 (−8.850 Kcal/mol) and (F) 833463-19-7 (−8.816 Kcal/mol). The motifs (A-G) are colored in A (green), (B) light pink, (C) white green, (D) Magenta, (E) Red, (F) Yellow and (G) Cyan respectively.
Figure 5.
Figure 5.
(a) & (b) show the interaction of top hit molecules Dataset 833463-10-8 and 833463-19-7 with RdRp of coronavirus for COVID-19.
Figure 6.
Figure 6.
Structure of the top identified lead compounds (Common scaffold is shown in bold).
Figure 7.
Figure 7.
Molecular dynamics simulation. RMSD of the backbone over the 20 ns MDS at 300 K of the complexes systems, the color codes are for (a) 3CLpro-2001083-69-6 (Black) and 3CLpro- 2001083-68-5 (Red), (b) RdRp-833463-10-8 (Blue) and RdRp-833463-19-7 (Magenta).
Figure 8.
Figure 8.
Molecular dynamics simulation. RMSF of the backbone over the 20 ns MDS at 300 K of the complexes systems, the color codes are for (a) 3CLpro-2001083-69-6 (Black) and 3CLpro- 2001083-68-5 (Red), (b) RdRp-833463-10-8 (Blue) and RdRp-833463-19-7(Magenta).
Figure 9.
Figure 9.
Molecular dynamics simulation. Radius gyrate of the backbone over the 20 ns MDS at 300 K of the complexes systems, the color codes are for (a) 3CLpro-2001083-69-6 (Black) and 3CLpro-2001083-68-5 (Red), (b) RdRp-833463-10-8 (Blue) and RdRp-833463-19-7(Magenta).
Figure 10.
Figure 10.
Number of hydrogen bonds of the complex of 3CLpro of coronavirus for COVID-19 with (a) 2001083-69-6 (Black) and (b) 2001083-68-5 (Red) and RdRp of coronavirus for COVID-19 with (c) 833463-10-8 and 833463-19-7(Magenta) as a function of time are retained or broken during simulation time scale 20 ns.
Figure 11.
Figure 11.
Molecular dynamics simulation. Variation in the ligands properties during the course of 20 ns MDS at 300 K, the color codes are for 2001083-69-6 (Black) and 2001083-68-5 (Red) in 3CLpro; 833463-10-8 (Blue) and 833463-19-7(Magenta) in RdRp.
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