Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors.

Human ezrin protein interacts with SARS-CoV S endodomain and restricts virus fusion, entry, and early events of infection. In general, their binding strength and their structural stability determines their successful entry into the host cells. However, the binding affinity of these two endodomains with the ezrin protein has been elusive due to a paucity of knowledge on the 3D structure. This study modelled the endodomains of both SARS-CoV-1 and SARS-CoV-2 and then docked these models with human ezrin protein. This study establishes that the modelled endodomains of both SARS-CoV-1 and SARS-Cov-2 consisted of three disulphide bridges for self-stabilization. Protein-protein docking listed four salt bridges with a higher buried surface area between ezrin-SARS-CoV-1 endodomain compared to that of ezrin-SARS-CoV-2 with six salt bridges with lower buried surface area. Molecular simulation of the ezrin-SARS-CoV-1 endodomain showed better structural stability with lower Root Mean Square Deviation score compared to that of ezrin-SARS-CoV-2 endodomain due to the substitution of alanine with cysteine residue. Protein-ligand docking studies confirmed better ezrin-drug interaction for quercetin, minocycline, calcifediol, calcitriol, selamectin, ivermectin and ergocalciferol. However, protein-ligand simulation confirmed strong drug-protein interaction during simulation for all the above-listed drugs except for ergocalciferol which could not establish its interaction with the protein during simulation. Strong drug binding within the active site pocket therefore restricts the interaction of viral endodomain and simultaneously stabilizes the ezrin protein. Furthermore, the higher stability between the ezrin after their interaction with the drug moiety could restrict the virus fusion and the infection. This study provides a basis for further development of these drug molecules to clinical trials aiming to identify potential drug molecules which can treat COVID-19 infection.

Risk stratifying gastric ulcers: development and validation of a scoring system.

Objective: Debate is ongoing regarding the need for universal endoscopic follow-up to ensure gastric ulcer healing. We aimed to assess the value of follow-up oesophago-gastro-duodenoscopies (OGDs) for gastric ulcer healing and stratify patients according to risk of malignancy by developing a risk score. Design/method: All patients in National Health Service (NHS) Lothian with an index OGD and a diagnosis of gastric ulcer between 1 January 2014 and 31 December 2018 were identified. Data were analysed with logistic regression to identify factors significantly associated with a diagnosis of cancer; a risk score was derived and externally validated. Results: 778 patients were identified and 60.3% (469/778) of patients had a follow-up OGD. 8.6% (66/778) of patients were diagnosed with cancer. No cases of cancer were found on follow-up OGD of a benign appearing ulcer with negative biopsies. Macroscopic suspicion of malignancy was present at index OGD in 100% (3/3) of those diagnosed with cancer on subsequent OGDs. Older age (p=0.014), increased ulcer size (p<0.001) and non-antral location (p=0.030) were significantly associated with malignancy. A risk score (area under the curve (AUC) 0.868, p<0.001, minimum score=0, maximum score=6) was derived from these variables. 78.0% of patients with malignant ulcers scored ≥3, only 15.8% with benign ulcers scored ≥3 (negative predictive value (NPV) 97.4%). External validation yielded an AUC of 0.862 (p<0.001) and NPV of 98.6%; 84.0% of those with malignant ulcers scored ≥3. Conclusion: Ulcers with a combination of macroscopically benign appearances, at least six negative biopsies and a low risk score do not necessarily need endoscopic follow-up.