Repurposing Remdesivir for COVID-19: Computational Drug Design Targeting SARS-CoV-2 RNA Polymerase and Main Protease using Molecular Dynamics Approach (preprint)

The coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory illness that has become a global health crisis with new variants, an unprecedented number of infections, and deaths and demands urgent manufacturing of potent therapeutics. Despite the success of vaccination campaigns around the globe, there is no particular therapeutics approved to date for efficiently treating infected individuals. Repositioning or repurposing previously effective antivirals against RNA viruses to treat COVID-19 patients is a feasible option. Remdesivir is a broad-spectrum antiviral drug that the Food and Drug Administration (FDA) licenses for treating COVID-19 patients who are critically ill patients. Remdesivir's low efficacy, which has been shown in some clinical trials, possible adverse effects, and dose-related toxicities are issues with its use in clinical use. Our study aimed to design potent derivatives of remdesivir through the functional group modification of the parent drug targeting RNA-dependent RNA polymerase (RdRp) and main protease (MPro) of SARS-CoV-2. The efficacy and stability of the proposed derivatives were assessed by molecular docking and extended molecular dynamics simulation analyses. Furthermore, the pharmacokinetic activity was measured to ensure the safety and drug potential of the designed derivatives. The derivatives were non-carcinogenic, chemically reactive, highly interactive, and stable with the target proteins. D-CF3 is one of the designed derivatives that finally showed stronger interaction than the parent drug, according to the docking and dynamics simulation analyses, with both target proteins. However, in vitro and in vivo investigations are guaranteed to validate the findings in the future. Keywords: SARS-CoV-2; RNA-dependent RNA polymerase (RdRp); Main protease (MPro); Remdesivir; Modified derivatives; Molecular docking; Molecular dynamics simulation.

OCR for TIFF Compressed Document Images Directly in Compressed Domain Using Text segmentation and Hidden Markov Model

In today's technological era, document images play an important and integral part in our day to day life, and specifically with the surge of Covid-19, digitally scanned documents have become key source of communication, thus avoiding any sort of infection through physical contact. Storage and transmission of scanned document images is a very memory intensive task, hence compression techniques are being used to reduce the image size before archival and transmission. To extract information or to operate on the compressed images, we have two ways of doing it. The first way is to decompress the image and operate on it and subsequently compress it again for the efficiency of storage and transmission. The other way is to use the characteristics of the underlying compression algorithm to directly process the images in their compressed form without involving decompression and re-compression. In this paper, we propose a novel idea of developing an OCR for CCITT (The International Telegraph and Telephone Consultative Committee) compressed machine printed TIFF document images directly in the compressed domain. After segmenting text regions into lines and words, HMM is applied for recognition using three coding modes of CCITT-horizontal, vertical and the pass mode. Experimental results show that OCR on pass modes give a promising results. © 2022 IEEE.

In-silico investigation of phytochemicals from Asparagus racemosus as plausible antiviral agent in COVID-19.

COVID-19 has ravaged the world and is the greatest of pandemics in human history, in the absence of treatment or vaccine the mortality and morbidity rates are very high. The present investigation was undertaken to screen and identify the potent leads from the Indian Ayurvedic herb, Asparagus racemosus (Willd.) against SARS-CoV-2 using molecular docking and dynamics studies. The docking analysis was performed on the Glide module of Schrödinger suite on two different proteins from SARS-CoV-2 viz. NSP15 Endoribonuclease and spike receptor-binding domain. Asparoside-C, Asparoside-D and Asparoside -F were found to be most effective against both the proteins as confirmed through their docking score and affinity. Further, the 100 ns molecular dynamics study also confirmed the potential of these compounds from reasonably lower root mean square deviations and better stabilization of Asparoside-C and Asparoside-F in spike receptor-binding domain and NSP15 Endoribonuclease respectively. MM-GBSA based binding free energy calculations also suggest the most favourable binding affinities of Asparoside-C and Asparoside-F with binding energies of -62.61 and -55.19 Kcal/mol respectively with spike receptor-binding domain and NSP15 Endoribonuclease. HighlightsAsparagus racemosus have antiviral potentialPhytochemicals of Shatavari showed promising in-silico docking and MD resultsAsparaoside-C and Asparoside-F has good binding with target proteinsAsparagus racemosus holds promise as SARS-COV-2 (S) and (N) proteins inhibitor Communicated by Ramaswamy H. Sarma.

COVID-19 outcomes in persons with multiple sclerosis treated with rituximab.

BACKGROUND: Outcomes of COVID-19 in PwMS (persons with Multiple Sclerosis) on immunosuppressive therapies, particularly B-cell depletors, can be unpredictable. There has been a concern for postponing or avoiding use of Rituximab (RTX) during the COVID-19 pandemic. We report the course and outcomes of COVID-19 in PwMS receiving RTX. METHODS: PwMS receiving RTX who contracted COVID-19 were closely monitored by tele-consultation and/or evaluated during hospital visits. Those requiring hospitalization for oxygen therapy or admission to ICU or expiring due to COVID-19 were considered to have severe disease. Those without desaturation and manageable at home were considered to have mild disease. Disease course and outcomes were noted. RESULTS: Twelve out of 62 (19.4%) PwMS on RTX therapy developed COVID-19. Four (age 35-49 years; mean 43.5) had severe COVID; three of whom had Secondary Progressive MS (SPMS). One PwMS expired. Two had prolonged fever lasting >1 month. One demonstrated features of SARS-CoV-2 reactivation. Interval from last RTX infusion (average dose 750 mg) to COVID-19 onset ranged 1-4 (mean 3.7) months. Eight PwMS had mild COVID-19 (age 26-54 years; mean 37.7); six had RRMS and two SPMS. RTX dose was lower (average dose 625 mg) and infusion to COVID-19 onset duration was longer, ranging 4-20 (mean 9.5) months. Four patients, two each from mild and severe COVID-19 groups had neurological deterioration, but none had true relapses. CONCLUSION: RTX treated PwMS may have unpredictable disease outcomes if they contract COVID-19, but may be at risk of severe disease and persistent infection. In our series higher age, SPMS, shorter interval from RTX infusion to COVID-19 onset and higher dose of RTX were noted amongst those developing severe disease. RTX should be use cautiously during the COVID-19 pandemic and if unavoidable, less frequent and lower doses should be considered. Patients receiving RTX must be counselled to follow strict COVID-19 preventive measures.

Sars-cov-2 host entry and replication inhibitors from Indian ginseng: an in-silico approach.

COVID-19 has ravaged the world and is the greatest of pandemics in modern human history, in the absence of treatment or vaccine, the mortality and morbidity rates are very high. The present investigation identifies potential leads from the plant Withania somnifera (Indian ginseng), a well-known antiviral, immunomodulatory, anti-inflammatory and a potent antioxidant plant, using molecular docking and dynamics studies. Two different protein targets of SARS-CoV-2 namely NSP15 endoribonuclease and receptor binding domain of prefusion spike protein from SARS-CoV-2 were targeted. Molecular docking studies suggested Withanoside X and Quercetin glucoside from W. somnifera have favorable interactions at the binding site of selected proteins, that is, 6W01 and 6M0J. The top-ranked phytochemicals from docking studies, subjected to 100 ns molecular dynamics (MD) suggested Withanoside X with the highest binding free energy (ΔGbind = -89.42 kcal/mol) as the most promising inhibitor. During MD studies, the molecule optimizes its conformation for better fitting with the receptor active site justifying the high binding affinity. Based on proven therapeutic, that is, immunomodulatory, antioxidant and anti-inflammatory roles and plausible potential against n-CoV-2 proteins, Indian ginseng could be one of the alternatives as an antiviral agent in the treatment of COVID 19. Communicated by Ramaswamy H. Sarma.

Computational and network pharmacology studies of Phyllanthus emblica to tackle SARS-CoV-2.

Background: Since December 2019, SARS-CoV-2 had been a significant threat globally, which has accounted for about two million deaths. Several types of research are undergoing and have reported the significant role of repurposing existing drugs and natural lead in the treatment of COVID-19. The plant Phyllanthus emblica (Synonym-Emblica officinalis) (Euphorbiaceae) is a rich source of vitamin C, and its use as an antiviral agent has been well established. Purpose: The present study was undertaken to investigate the potency of the several components of Phyllanthus emblica against three protein targets of 2019-nCoV viz. NSP15 endoribonuclease, main protease, and receptor binding domain of prefusion spike protein using molecular docking and dynamics studies. Methods: The docking simulation studies were carried out using Schrödinger maestro 2018-1 MM share version, while dynamics studies were conducted to understand the binding mechanism and the complexes' stability studies. Results: Out of sixty-six tested compounds, Chlorogenic acid, Quercitrin, and Myricetin were most effective in showing the highest binding energy against selected protein targets of SARS-CoV-2. The network pharmacology analysis study confirmed these compounds' role in modulating the immune response, inflammatory cascade, and cytokine storm through different signaling pathways. Conclusion: Current pharmacoinformatic approach shows possible role of Phyllanthus emblica in the treatment and management of COVID-19.

Computational assessment of saikosaponins as adjuvant treatment for COVID-19: molecular docking, dynamics, and network pharmacology analysis.

Saikosaponins are major biologically active triterpenoids, usually as glucosides, isolated from Traditional Chinese Medicines (TCM) such as Bupleurum spp., Heteromorpha spp., and Scrophularia scorodonia with their antiviral and immunomodulatory potential. This investigation presents molecular docking, molecular dynamics simulation, and free energy calculation studies of saikosaponins as adjuvant therapy in the treatment for COVID19. Molecular docking studies for 23 saikosaponins on the crystal structures of the extracellular domains of human lnterleukin-6 receptor (IL6), human Janus Kinase-3 (JAK3), and dehydrogenase domain of Cylindrospermum stagnale NADPH-oxidase 5 (NOX5) were performed, and selected protein-ligand complexes were subjected to 100 ns molecular dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Molecular docking and molecular dynamics simulation studies revealed that IL6 in complex with Saikosaponin_U and Saikosaponin_V, JAK3 in complex with Saikosaponin_B4 and Saikosaponin_I, and NOX5 in complex with Saikosaponin_BK1 and Saikosaponin_C have good docking and molecular dynamics profiles. However, the Janus Kinase-3 is the best interacting partner for the saikosaponin compounds. The network pharmacology analysis suggests saikosaponins interact with the proteins CAT Gene CAT (Catalase) and Checkpoint kinase 1 (CHEK1); both of these enzymes play a major role in cell homeostasis and DNA damage during infection, suggesting a possible improvement in immune response toward COVID-19.

COVID-19-related strokes are associated with increased mortality and morbidity: A multicenter comparative study from Bengaluru, South India.

BACKGROUND: COVID-19-related strokes are increasingly being diagnosed across the world. Knowledge about the clinical profile, imaging findings, and outcomes is still evolving. Here we describe the characteristics of a cohort of 62 COVID-19-related stroke patients from 13 hospitals, from Bangalore city, south India. OBJECTIVE: To describe the clinical profile, neuroimaging findings, interventions, and outcomes in COVID-19-related stroke patients. METHODS: This is a multicenter retrospective study of all COVID-19-related stroke patients from 13 hospitals from south India; 1st June 2020-31st August 2020. The demographic, clinical, laboratory, and neuroimaging data were collected along with treatment administered and outcomes. SARS-CoV-2 infection was confirmed in all cases by RT-PCR testing. The data obtained from the case records were entered in SPSS 25 for statistical analysis. RESULTS: During the three-month period, we had 62 COVID-19-related stroke patients, across 13 centers; 60 (97%) had ischemic strokes, while 2 (3%) had hemorrhagic strokes. The mean age of patients was 55.66 ± 13.20 years, with 34 (77.4%) males. Twenty-six percent (16/62) of patients did not have any conventional risk factors for stroke. Diabetes mellitus was seen in 54.8%, hypertension was present in 61.3%, coronary artery disease in 8%, and atrial fibrillation in 4.8%. Baseline National Institutes of Health Stroke Scale score was 12.7 ± 6.44. Stroke severity was moderate (National Institutes of Health Stroke Scale 5-15) in 27 (61.3%) patients, moderate to severe (National Institutes of Health Stroke Scale 16-20) in 13 (20.9%) patients and severe (National Institutes of Health Stroke Scale 21-42) in 11 (17.7%) patients. According to TOAST classification, 48.3% was stroke of undetermined etiology, 36.6% had large artery atherosclerosis, 10% had small vessel occlusion, and 5% had cardioembolic strokes. Three (5%) received intravenous thrombolysis with tenecteplase 0.2 mg/kg and 3 (5%) underwent mechanical thrombectomy, two endovascular and one surgical. Duration of hospital stay was 16.16 ± 6.39 days; 21% (13/62) died in hospital, while 37 (59.7%) had a modified Rankin score of 3-5 at discharge. Hypertension, atrial fibrillation, and higher baseline National Institutes of Health Stroke Scale scores were associated with increased mortality. A comparison to 111 historical controls during the non-COVID period showed a higher proportion of strokes of undetermined etiology, higher mortality, and higher morbidity in COVID-19-related stroke patients. CONCLUSION: COVID-19-related strokes are increasingly being recognized in developing countries, like India. Stroke of undetermined etiology appears to be the most common TOAST subtype of COVID-19-related strokes. COVID-19-related strokes were more severe in nature and resulted in higher mortality and morbidity. Hypertension, atrial fibrillation, and higher baseline National Institutes of Health Stroke Scale scores were associated with increased mortality.

Identification of bioactive compounds from Glycyrrhiza glabra as possible inhibitor of SARS-CoV-2 spike glycoprotein and non-structural protein-15: a pharmacoinformatics study.

At present, the world is facing a pandemic named as COVID-19, caused by SARS-CoV-2. Traditional Chinese medicine has recommended the use of liquorice (Glycyrrhiza species) in the treatment of infections caused by SARS-CoV-2. Therefore, the present investigation was carried out to identify the active molecule from the liquorice against different protein targets of COVID-19 using an in-silico approach. The molecular docking simulation study of 20 compounds along with two standard antiviral drugs (Lopinavir and Rivabirin) was carried out with the help of Autodock vina software using two protein targets from COVID-19 i.e. spike glycoprotein (PDB ID: 6VSB) and Non-structural Protein-15 (Nsp15) endoribonuclease (PDB ID: 6W01). From the observed binding energy and the binding interactions, glyasperin A showed high affinity towards Nsp15 endoribonuclease with uridine specificity, while glycyrrhizic acid was found to be best suited for the binding pocket of spike glycoprotein and also prohibited the entry of the virus into the host cell. Further, the dynamic behavior of the best-docked molecules inside the spike glycoprotein and Nsp15 endoribonuclease were explored through all-atoms molecular dynamics (MD) simulation study. Several parameters from the MD simulation have substantiated the stability of protein-ligand stability. The binding free energy of both glyasperin A and glycyrrhizic acid was calculated from the entire MD simulation trajectory through the MM-PBSA approach and found to high binding affinity towards the respective protein receptor cavity. Thus, glyasperin A and glycyrrhizic acid could be considered as the best molecule from liquorice, which could find useful against COVID-19. Communicated by Ramaswamy H. Sarma.

Experience from a Singapore tertiary hospital with restructuring of a vascular surgery practice in response to national and institutional policies during the COVID-19 pandemic.

Singapore was one of the first countries to be affected by COVID-19, with the index patient diagnosed on January 23, 2020. For 2 weeks in February, we had the highest number of COVID-19 cases behind China. In this article, we summarize the key national and institutional policies that were implemented in response to COVID-19. We also describe in detail, with relevant data, how our vascular surgery practice has changed because of these policies and COVID-19. We show that with a segregated team model, the vascular surgery unit can still function while reducing risk of cross-contamination. We explain the various strategies adopted to reduce outpatient and inpatient volume. We provide a detailed breakdown of the type of vascular surgical cases that were performed during the COVID-19 pandemic and compare it with preceding months. We discuss our operating room and personal protective equipment protocols in managing a COVID-19 patient and share how we continue surgical training amid the pandemic. We also discuss the challenges we might face in the future as COVID-19 regresses.