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

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.

Cholesterol solubilization by oxo derivatives of selected bile acids and their membranotoxicity

This study is concerned with the effect of the structure of bile acids on the solubilization of cholesterol (cholesterol solubilizing capacity (CChm) and the equilibrium micellary solubilization of cholesterol (xChm)). It was found that the replacement of the hydroxy group in the bile acid molecule with an oxo group results in a decrease of the solubilization power of cholesterol. The examined bile acids form two linear groups at the plane of critical micellar concentration (CMC) and solubilization power of cholesterol (CChm or xChm). The group I is formed by bile acids with lower CMCs and higher cholesterol solubilites (deoxycholic (1), chenodeoxycholic (2), hyodeoxycholic (3), cholic (8), 12-oxolithocholic (4), and 7-oxolithocholic (5) acids). On the other hand, the group II is formed by bile acids with higher CMCs and lower cholesterol solubilites (7-oxodeoxycholic (9), 12-oxochenodeoxycholic (10), 12α-hydroxy-3,7-dioxocholanic (11), 7,12-dioxolithocholic (12), 3,7-dioxocholanic (6), and 3,12-dioxocholanic (7) acids). The common conformational characteristics of the bile acid molecules was determined (orientation of OH or oxo grups considered to the mean plane of the steroid skeleton). They form joint groups in the plane of CMC – (CChm or xChm), and the linear function (CChm or xChm) = f(CMC). The osmotic resistance of erythrocytes determines the membranotoxicity of bile acids. 12-Oxolithocholic acid represents the best compromise with regard to the solubilization of cholesterol and membranotoxicity.