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

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.

Ursodeoxycholic acid ameliorates cell migration retarded by the SARS-CoV-2 spike protein in BEAS-2B human bronchial epithelial cells

“…Membrane-bound UDCA may reduce the internalization of SARS-CoV-2 in the host cell [20] . Therefore, we investigated whether UDCA can prevent SP binding on ACE2.…”

“…Therefore, it is important to determine whether SARS-CoV-2 impairs airway epithelial cell migration, which can be attenuated by various molecules. UDCA interacts in two distinct regions of SP sequences, and may also bind to the cell membrane to inhibit SARS-CoV-2 entry into host cells [20] . However, the physiological effects of UDCA on airway epithelium regeneration remain poorly understood.…”

“…UDCA also interacts in two distinct regions of SP sequences. UDCA may remain bound to the membrane, inhibiting the entry of SARS-CoV-2 into the host cell [20] through reduced RBD–ACE2 binding [21] . However, the physiological effects of UDCA on airway epithelium regeneration remain poorly understood.…”

COVID-19 in Patients with Primary Biliary Cholangitis

“…Все пациенты в нашем исследовании получали терапию УДХК. В период пандемии неоднократно обсуждался возможный протективный эффект УДХК на риск заражения и тяжесть течения инфекции SARS-CoV-2 [13]. Интересно, что, по нашим данным, инфекция SARS-CoV-2 чаще выявлена у пациентов с ПБХ без ответа на терапию УДХК в анамнезе и именно эти пациенты чаще нуждались в кислородной поддержке при госпитализации по поводу СOVID-19.…”

“…Ранее было показано, что УДХК способна препятствовать внедрению SARS-CoV-2 в клетку человека за счет взаимодействия со Spike-белком и мембранной моделью SARS-CoV-2, нарушая взаимодействие вируса с его клетками-мишенями и препятствуя их инфицированию [13]. УДХК, эндогенная гидрофильная желчная кислота, является антиапоптотическим средством, оказывающим плейотропный, в том числе и противовоспалительный, эффект.…”