Interaction of Spike protein and lipid membrane of SARS-CoV-2 with Ursodeoxycholic acid, an in-silico analysis

Francisco Javier Rodal Canales,Carlos Alberto Matias-Cervantes,Margarito Martínez Cruz,María Teresa Hernández-Huerta,Eduardo Pérez-Campos Mayoral,Edgar Gustavo Ramos-Martínez,Luis Manuel Sánchez Navarro,Eduardo Pérez-Campos,Edgar Zenteno,Carlos Romero Díaz,Laura Pérez-Campos Mayoral,Eli Cruz Parada

doi:10.1038/s41598-021-01705-5

Francisco Javier Rodal Canales, Carlos Alberto Matias-Cervantes + Show 10 more

Open Access

https://doi.org/10.1038/s41598-021-01705-5

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Abstract

Numerous repositioned drugs have been sought to decrease the severity of SARS-CoV-2 infection. It is known that among its physicochemical properties, Ursodeoxycholic Acid (UDCA) has a reduction in surface tension and cholesterol solubilization, it has also been used to treat cholesterol gallstones and viral hepatitis. In this study, molecular docking was performed with the SARS-CoV-2 Spike protein and UDCA. In order to confirm this interaction, we used Molecular Dynamics (MD) in “SARS-CoV-2 Spike protein-UDCA”. Using another system, we also simulated MD with six UDCA residues around the Spike protein at random, naming this “SARS-CoV-2 Spike protein-6UDCA”. Finally, we evaluated the possible interaction between UDCA and different types of membranes, considering the possible membrane conformation of SARS-CoV-2, this was named “SARS-CoV-2 membrane-UDCA”. In the “SARS-CoV-2 Spike protein-UDCA”, we found that UDCA exhibits affinity towards the central region of the Spike protein structure of − 386.35 kcal/mol, in a region with 3 alpha helices, which comprises residues from K986 to C1032 of each monomer. MD confirmed that UDCA remains attached and occasionally forms hydrogen bonds with residues R995 and T998. In the presence of UDCA, we observed that the distances between residues atoms OG1 and CG2 of T998 in the monomers A, B, and C in the prefusion state do not change and remain at 5.93 ± 0.62 and 7.78 ± 0.51 Å, respectively, compared to the post-fusion state. Next, in “SARS-CoV-2 Spike protein-6UDCA”, the three UDCA showed affinity towards different regions of the Spike protein, but only one of them remained bound to the region between the region's heptad repeat 1 and heptad repeat 2 (HR1 and HR2) for 375 ps of the trajectory. The RMSD of monomer C was the smallest of the three monomers with a value of 2.89 ± 0.32, likewise, the smallest RMSF was also of the monomer C (2.25 ± 056). In addition, in the simulation of “SARS-CoV-2 membrane-UDCA”, UDCA had a higher affinity toward the virion-like membrane; where three of the four residues remained attached once they were close (5 Å, to the centre of mass) to the membrane by 30 ns. However, only one of them remained attached to the plasma-like membrane and this was in a cluster of cholesterol molecules. We have shown that UDCA interacts in two distinct regions of Spike protein sequences. In addition, UDCA tends to stay bound to the membrane, which could potentially reduce the internalization of SARS-CoV-2 in the host cell.

Highlights

Numerous repositioned drugs have been sought to decrease the severity of SARS-CoV-2 infection
When applying Molecular Dynamics (MD) to this structure, we observed that the Ursodeoxycholic Acid (UDCA) remained in the same position during the whole trajectory, and there were even moments when hydrogen bonds were formed with residues close to it (Table 2)
One of the regions which shown attraction is in the area with three alpha-helices of three monomers of the Spike protein, and the other, with a CYS1126 residue in a zone between the HR1 and heptad repeat 2 (HR2) regions

Summary

Introduction

Numerous repositioned drugs have been sought to decrease the severity of SARS-CoV-2 infection. In order to confirm this interaction, we used Molecular Dynamics (MD) in “SARS-CoV-2 Spike protein-UDCA”. In the simulation of “SARS-CoV-2 membrane-UDCA”, UDCA had a higher affinity toward the virion-like membrane; where three of the four residues remained attached once they were close (5 Å, to the centre of mass) to the membrane by 30 ns. SARS-CoV-2 is surrounded on average by 40 to 48 Spike (S) trimer proteins[10,11], these are heavily glycosylated and have three receptor-binding domains (RBDs), covered on top of the S trimer by the N-terminal domains (NTD)[12,13] These are mainly found in a closed prefusion conformation[8]. ERGIC is composed of approximately 58% phosphatidylcholine, 22% phosphatidylethanolamine, 3% phosphatidylserine, 10% phosphatidylinositol, 3% sphingomyelin, and 0.08% c holesterol[17]

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Conclusion