SARS-CoV-2 ORF8 dimerization and binding mode analysis with class I MHC: computational approaches to identify COVID-19 inhibitors.

SARS-CoV-2 encodes eight accessory proteins, one of which, ORF8, has a poorly conserved sequence with SARS-CoV and its role in viral pathogenicity has recently been identified. ORF8 in SARS-CoV-2 has a unique functional feature that allows it to form a dimer structure linked by a disulfide bridge between Cys20 and Cys20 (S-S). This study provides structural characterization of natural mutant variants as well as the identification of potential drug candidates capable of binding directly to the interchain disulfide bridge. The lead compounds reported in this work have a tendency to settle in the dimeric interfaces by direct interaction with the disulfide bridge. These molecules may disturb the dimer formation and may have an inhibition impact on its potential functional role in host immune evasion and virulence pathogenicity. This work provides detailed insights on the sequence and structural variability through computational mutational studies, as well as potent drug candidates with the ability to interrupt the intermolecular disulfide bridge formed between Cys20 and Cys20. Furthermore, the interactions of ORF8 peptides complexed with MHC-1 is studied, and the binding mode reveals that certain ORF8 peptides bind to MHC-1 in a manner similar to other viral peptides. Overall, this study is a narrative of various computational approaches used to provide detailed structural insights into SARS-CoV-2 ORF8 interchain disulfide bond disruptors.

Survey of healthcare worker perceptions of changes in infection control and antimicrobial stewardship practices in India and South Africa during the COVID-19 pandemic.

Objective: To identify perceptions and awareness of changes in IPC and AMS practices among healthcare workers (HCWs) during the COVID-19 pandemic in India and South Africa (SA). Method: A self-administered online survey which included participant demographics, knowledge and sources of COVID-19 infection, perceived risks and barriers, and self-efficacy. Data were analysed using descriptive statistics. Results: 321 responses (response rate: 89.2%); 131/321 (40.8%) from India and 190/321 (59.2%) from SA; male to female response rate was 3:2, with majority of respondents aged 40-49 (89/321, 27.7%) and 30-39 (87/321, 27.1%) years. Doctors comprised 47.9% (57/119) of respondents in India and 74.6% (135/181) in SA. Majority of respondents in India (93/119, 78.2%) and SA (132/181, 72.9%) were from the private and public sectors, respectively with more respondents in SA (123/174, 70.7%) than in India (38/104, 36.5%) were involved in antimicrobial prescribing. Respondents reported increased IPC practices since the pandemic and noted need for more training on case management, antibiotic and personal protective equipment (PPE) use. While they noted increased antibiotic prescribing since the pandemic; they did not generally associate their practice with such increase. A willingness to be vaccinated, when vaccination becomes available, was expressed by 203/258 (78.7%) respondents. Conclusions: HCWs reported improved IPC practices and changes in antibiotic prescribing during the COVID-19 pandemic. Targeted education on correct use of PPE was an identified gap. Although HCWs expressed concerns about antimicrobial resistance, their self-perceived antibiotic prescribing practices seemed unchanged. Additional studies in other settings could explore how our findings fit other contexts.

Intrinsically disordered proteins in viral pathogenesis and infections.

Disordered proteins serve a crucial part in many biological processes that go beyond the capabilities of ordered proteins. A large number of virus-encoded proteins have extremely condensed proteomes and genomes, which results in highly disordered proteins. The presence of these IDPs allows them to rapidly adapt to changes in their biological environment and play a significant role in viral replication and down-regulation of host defense mechanisms. Since viruses undergo rapid evolution and have a high rate of mutation and accumulation in their proteome, IDPs' insights into viruses are critical for understanding how viruses hijack cells and cause disease. There are many conformational changes that IDPs can adopt in order to interact with different protein partners and thus stabilize the particular fold and withstand high mutation rates. This chapter explains the molecular mechanism behind viral IDPs, as well as the significance of recent research in the field of IDPs, with the goal of gaining a deeper comprehension of the essential roles and functions played by viral proteins.

Viral hijacking mechanism in humans through protein-protein interactions.

Numerous viruses have evolved mechanisms to inhibit or alter the host cell's apoptotic response as part of their coevolution with their hosts. The analysis of virus-host protein interactions require an in-depth understanding of both the viral and host protein structures and repertoires, as well as evolutionary mechanisms and pertinent biological facts. Throughout the course of a viral infection, there is constant battle for binding between virus and cellular proteins. Exogenous interfaces facilitating viral-host interactions are well known for constantly targeting and suppressing endogenous interfaces mediating intraspecific interactions, such as viral-viral and host-host connections. In these interactions, the protein-protein interactions (PPIs), are mostly shown as networks (protein interaction networks, PINs), with proteins represented as nodes and their interactions represented as edges. Host proteins with a higher degree of connectivity are more likely to interact with viral proteins. Due to technical advancements, three-dimensional interactions may now be visualized computationally utilizing molecular modeling and cryo-EM approaches. The uniqueness of viral domain repertoires, their evolution, and their activities during viral infection make viruses fascinating models for research. This chapter aims to provide readers a complete picture of the viral hijacking mechanism in protein-protein interactions.

Interventional research to tackle antimicrobial resistance in Low Middle Income Countries in the era of the COVID-19 pandemic: lessons in resilience from an international consortium.

This article summarizes the consequences of the COVID-19 pandemic, on an international project to tackle antimicrobial resistance (AMR). The research leadership and process, the access to data, and stakeholders were deeply disrupted by the national and international response to the pandemic, including the interruption of healthcare delivery, lockdowns, and quarantines. The key principles to deliver the research through the pandemic were mainly the high degree of interdisciplinary engagement with integrated teams, and equitable partnership across sites with capacity building and leadership training. The level of preexisting collaboration and partnership were also keys to sustaining connections and involvements throughout the pandemic. The pandemic offered opportunities for realigning research priorities. Flexibility in funding timelines and projects inputs are required to accommodate variance introduced by external factors. The current models for research collaboration and funding need to be critically evaluated and redesigned to retain the innovation that was shown to be successful through this pandemic.

Immunological insights of selectins in human disease mechanism.

Selectin enzymes are glycoproteins and are an important adhesion molecule in the mammalian immune system, especially in the inflammatory response and the healing process of tissues. Selectins play an important role in a variety of biological processes, including the rolling of leukocytes in endothelial cells, a process known as the adhesion cascade. It has recently been discovered and reported that the selectin mechanism plays a role in cancer and thrombosis disease. This process begins with non-covalent interactions-based selectin-ligand binding and the glycans play a role as a connector between cancer cells and the endothelium in this process. The selectin mechanism is critical for the immune system, but it is also involved in disease mechanisms, earning the selectins the nickname "Selectins-The Two Dr. Jekyll and Mr. Hyde Faces". As a result, the drug for selectins should have a multifaceted role and be a dynamic molecule that targets the disease mechanism specifically. This chapter explores the role of selectins in the disease mechanism at the mechanism level that provides the impact for identifying the selectin inhibitors. Overall, this chapter provides the molecular level insights on selectins, their ligands, involvement in normal and disease mechanisms.

Artificial intelligence and machine learning approaches for drug design: challenges and opportunities for the pharmaceutical industries.

The global spread of COVID-19 has raised the importance of pharmaceutical drug development as intractable and hot research. Developing new drug molecules to overcome any disease is a costly and lengthy process, but the process continues uninterrupted. The critical point to consider the drug design is to use the available data resources and to find new and novel leads. Once the drug target is identified, several interdisciplinary areas work together with artificial intelligence (AI) and machine learning (ML) methods to get enriched drugs. These AI and ML methods are applied in every step of the computer-aided drug design, and integrating these AI and ML methods results in a high success rate of hit compounds. In addition, this AI and ML integration with high-dimension data and its powerful capacity have taken a step forward. Clinical trials output prediction through the AI/ML integrated models could further decrease the clinical trials cost by also improving the success rate. Through this review, we discuss the backend of AI and ML methods in supporting the computer-aided drug design, along with its challenge and opportunity for the pharmaceutical industry. From the available information or data, the AI and ML based prediction for the high throughput virtual screening. After this integration of AI and ML, the success rate of hit identification has gained a momentum with huge success by providing novel drugs.

Structural Understanding of SARS-CoV-2 Drug Targets, Active Site Contour Map Analysis and COVID-19 Therapeutics.

The pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2), is responsible for multiple worldwide lockdowns, an economic crisis, and a substantial increase in hospitalizations for viral pneumonia along with respiratory failure and multiorgan dysfunctions. Recently, the first few vaccines were approved by World Health Organization (WHO) and can eventually save millions of lives. Even though, few drugs are used in emergency like Remdesivir and several other repurposed drugs, still there is no approved drug for COVID-19. The coronaviral encoded proteins involved in host-cell entry, replication, and host-cell invading mechanism are potential therapeutic targets. This perspective review provides the molecular overview of SARS-CoV-2 life cycle for summarizing potential drug targets, structural insights, active site contour map analyses of those selected SARS-CoV-2 protein targets for drug discovery, immunology, and pathogenesis.

High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2 Nsp3.

SARS-CoV-2 encodes the Mac1 domain within the large nonstructural protein 3 (Nsp3), which has an ADP-ribosylhydrolase activity conserved in other coronaviruses. The enzymatic activity of Mac1 makes it an essential virulence factor for the pathogenicity of coronavirus (CoV). They have a regulatory role in counteracting host-mediated antiviral ADP-ribosylation, which is unique part of host response towards viral infections. Mac1 shows highly conserved residues in the binding pocket for the mono and poly ADP-ribose. Therefore, SARS-CoV-2 Mac1 enzyme is considered as an ideal drug target and inhibitors developed against them can possess a broad antiviral activity against CoV. ADP-ribose-1 phosphate bound closed form of Mac1 domain is considered for screening with large database of ZINC. XP docking and QPLD provides strong potential lead compounds, that perfectly fits inside the binding pocket. Quantum mechanical studies expose that, substrate and leads have similar electron donor ability in the head regions, that allocates tight binding inside the substrate-binding pocket. Molecular dynamics study confirms the substrate and new lead molecules presence of electron donor and acceptor makes the interactions tight inside the binding pocket. Overall binding phenomenon shows both substrate and lead molecules are well-adopt to bind with similar binding mode inside the closed form of Mac1.

Lipid profile as an indicator of COVID-19 severity: A systematic review and meta-analysis.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is a global pandemic. Studies reported dyslipidemia in patients with COVID-19. Herein, we conducted a systematic review and meta-analysis of published articles to evaluate the association of the lipid profile with the severity and mortality in COVID-19 patients. METHODS: PubMed/Medline, Europe PMC, and Google Scholar were searched for studies published between January 1, 2020 and January 13, 2021. Random or Fixed effects models were used to calculate the mean difference (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using Cochran's Q test and I2 statistics. RESULTS: This meta-analysis included 19 studies. Of which, 12 studies were categorized by severity, 04 studies by mortality, and 03 studies by both severity and mortality. Our findings revealed significantly decreased levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the severe group when compared with the non-severe group in a random effect model. Similarly, random effect model results demonstrated significantly lower levels of HDL-C and LDL-C in the non-survivor group when compared with the survivor group. The level of TC was also found to be decreased in the non-survivor group when compared to the survivor group in a fixed-effect model. CONCLUSION: In conclusion, the lipid profile is associated with both the severity and mortality in COVID-19 patients. Hence, the lipid profile may be used for assessing the severity and prognosis of COVID-19. PROSPERO REGISTRATION NUMBER: CRD42021216316.

Rapid diagnostic testing for antimicrobial stewardship: Utility in Asia Pacific.

Rapid diagnostic testing (RDT) can provide prompt, accurate identification of infectious organisms and be a key component of antimicrobial stewardship (AMS) programs. However, their use is less widespread in Asia Pacific than western countries. Cost can be prohibitive, particularly in less resource-replete settings. A selective approach is required, possibly focusing on the initiation of antimicrobials, for differentiating bacterial versus viral infections and identifying locally relevant tropical diseases. Across Asia Pacific, more data are needed on RDT use within AMS, focusing on the impact on antimicrobial usage, patient morbidity and mortality, and cost effectiveness. Moreover, in the absence of formal guidelines, regional consensus statements to guide clinical practice are warranted. These will provide a regionally relevant definition for RDT; greater consensus on its role in managing infections; advice on implementation and overcoming barriers; and guidance on optimizing human resource capacity. By addressing these issues, the outcomes of AMS programs should improve.

Macro level influences on strategic responses to the COVID-19 pandemic - an international survey and tool for national assessments.

BACKGROUND: Variation in the approaches taken to contain the SARS-CoV-2 (COVID-19) pandemic at country level has been shaped by economic and political considerations, technical capacity, and assumptions about public behaviours. To address the limited application of learning from previous pandemics, this study aimed to analyse perceived facilitators and inhibitors during the pandemic and to inform the development of an assessment tool for pandemic response planning. METHODS: A cross-sectional electronic survey of health and non-health care professionals (5 May - 5 June 2020) in six languages, with respondents recruited via email, social media and website posting. Participants were asked to score inhibitors (-10 to 0) or facilitators (0 to +10) impacting country response to COVID-19 from the following domains - Political, Economic, Sociological, Technological, Ecological, Legislative, and wider Industry (the PESTELI framework). Participants were then asked to explain their responses using free text. Descriptive and thematic analysis was followed by triangulation with the literature and expert validation to develop the assessment tool, which was then compared with four existing pandemic planning frameworks. RESULTS: 928 respondents from 66 countries (57% health care professionals) participated. Political and economic influences were consistently perceived as powerful negative forces and technology as a facilitator across high- and low-income countries. The 103-item tool developed for guiding rapid situational assessment for pandemic planning is comprehensive when compared to existing tools and highlights the interconnectedness of the 7 domains. CONCLUSIONS: The tool developed and proposed addresses the problems associated with decision making in disciplinary silos and offers a means to refine future use of epidemic modelling.

Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19.

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.

A road-map for addressing antimicrobial resistance in low- and middle-income countries: lessons learnt from the public private participation and co-designed antimicrobial stewardship programme in the State of Kerala, India.

BACKGROUND: The global concern over antimicrobial resistance (AMR) is gathering pace. Low- and middle-income countries (LMICs) are at the epicentre of this growing public health threat and governmental and healthcare organizations are at different stages of implementing action plans to tackle AMR. The South Indian state of Kerala was one of the first in India to implement strategies and prioritize activities to address this public health threat. STRATEGIES: Through a committed and collaborative effort from all healthcare related disciplines and its professional societies from both public and private sector, the Kerala Public Private Partnership (PPP) has been able to deliver a state-wide strategy to tackle AMR A multilevel strategic leadership model and a multilevel implementation approach that included developing state-wide antibiotic clinical guidelines, a revision of post-graduate and undergraduate medical curriculum, and a training program covering all general practitioners within the state the PPP proved to be a successful model for ensuring state-wide implementation of an AMR action plan. Collaborative work of multi-professional groups ensured co-design and development of disease based clinical treatment guidelines and state-wide infection prevention policy. Knowledge exchange though international and national platforms in the form of workshops for sharing of best practices is critical to success. Capacity building at both public and private institutions included addressing practical and local solutions to the barriers e.g. good antibiotic prescription practices from primary to tertiary care facility and infection prevention at all levels. CONCLUSION: Through 7 years of stakeholder engagement, lobbying with government, and driving change through co-development and implementation, the PPP successfully delivered an antimicrobial stewardship plan across the state. The roadmap for the implementation of the Kerala PPP strategic AMR plan can provide learning for other states and countries aiming to implement action plans for AMR.

Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease.

The recent pandemic outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raised global health and economic concerns. Phylogenetically, SARS-CoV-2 is closely related to SARS-CoV, and both encode the enzyme main protease (Mpro/3CLpro), which can be a potential target inhibiting viral replication. Through this work, we have compiled the structural aspects of Mpro conformational changes, with molecular modeling and 1-µs MD simulations. Long-scale MD simulation resolves the mechanism role of crucial amino acids involved in protein stability, followed by ensemble docking which provides potential compounds from the Traditional Chinese Medicine (TCM) database. These lead compounds directly interact with active site residues (His41, Gly143, and Cys145) of Mpro, which plays a crucial role in the enzymatic activity. Through the binding mode analysis in the S1, S1', S2, and S4 binding subsites, screened compounds may be functional for the distortion of the oxyanion hole in the reaction mechanism, and it may lead to the inhibition of Mpro in SARS-CoV-2. The hit compounds are naturally occurring compounds; they provide a sustainable and readily available option for medical treatment in humans infected by SARS-CoV-2. Henceforth, extensive analysis through molecular modeling approaches explained that the proposed molecules might be promising SARS-CoV-2 inhibitors for the inhibition of COVID-19, subjected to experimental validation.

Critical Care for COVID-19 Affected Patients: Updated Position Statement of the Indian Society of Critical Care Medicine.

The management of coronavirus disease-2019 (COVID-19) is witnessing a change as we learn more about the pathophysiology and the severity of the disease. Several randomized controlled trials (RCTs) and meta-analysis have been published over the last few months. Several interventions and therapies which showed promise in the initial days of the pandemic have subsequently failed to show benefit in well-designed trials. Understanding of the methods of oxygen delivery and ventilation have also evolved over the past few months. The Indian Society of Critical Care Medicine (ISCCM) has reviewed the evidence that has emerged since the publication of its position statement in May and has put together an addendum of updated evidence. How to cite this article: Mehta Y, Chaudhry D, Abraham OC, Chacko J, Divatia J, Jagiasi B, et al. Critical Care for COVID-19 Affected Patients: Position Statement of the Indian Society of Critical Care Medicine. Indian J Crit Care Med 2020;24(Suppl 5):S225-S230.

Computational studies reveal piperine, the predominant oleoresin of black pepper (Piper nigrum) as a potential inhibitor of SARS-CoV-2 (COVID-19)

In this study, we screened 26 bioactive compounds present in various spices for activity against SARS-CoV-2 using molecular docking. Results showed that piperine, present in black pepper had a high binding affinity (-7.0 kCal/mol) than adenosine monophosphate (-6.4 kCal/mol) towards the RNA-binding pocket of the nucleocapsid. Molecular dynamics simulation of the docked complexes confirmed the stability of piperine docked to nucleocapsid protein as a potential inhibitor of the RNA-binding site. Therefore, piperine seems to be potential candidate to inhibit the packaging of RNA in the nucleocapsid and thereby inhibiting the viral proliferation. This study suggests that consumption of black pepper may also help to combat SARS-CoV-2 directly through possible antiviral effects, besides its immunomodulatory functions.

Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of ayurvedic medicinal plants - Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) - a molecular docking study.

COVID-19 (Coronavirus disease 2019) is a transmissible disease initiated and propagated through a new virus strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) since 31st December 2019 in Wuhan city of China and the infection has outspread globally influencing millions of people. Here, an attempt was made to recognize natural phytochemicals from medicinal plants, in order to reutilize them against COVID-19 by the virtue of molecular docking and molecular dynamics (MD) simulation study. Molecular docking study showed six probable inhibitors against SARS-CoV-2 Mpro (Main protease), two from Withania somnifera (Ashwagandha) (Withanoside V [10.32 kcal/mol] and Somniferine [9.62 kcal/mol]), one from Tinospora cordifolia (Giloy) (Tinocordiside [8.10 kcal/mol]) and three from Ocimum sanctum (Tulsi) (Vicenin [8.97 kcal/mol], Isorientin 4'-O-glucoside 2″-O-p-hydroxybenzoagte [8.55 kcal/mol] and Ursolic acid [8.52 kcal/mol]). ADMET profile prediction showed that the best docked phytochemicals from present work were safe and possesses drug-like properties. Further MD simulation study was performed to assess the constancy of docked complexes and found stable. Hence from present study it could be suggested that active phytochemicals from medicinal plants could potentially inhibit Mpro of SARS-CoV-2 and further equip the management strategy against COVID-19-a global contagion. HighlightsHolistic approach of Ayurvedic medicinal plants to avenge against COVID-19 pandemic.Active phytoconstituents of Ayurvedic medicinal plants Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) predicted to significantly hinder main protease (Mpro or 3Clpro) of SARS-CoV-2.Through molecular docking and molecular dynamic simulation study, Withanoside V, Somniferine, Tinocordiside, Vicenin, Ursolic acid and Isorientin 4'-O-glucoside 2″-O-p-hydroxybenzoagte were anticipated to impede the activity of SARS-CoV-2 Mpro.Drug-likeness and ADMET profile prediction of best docked compounds from present study were predicted to be safe, drug-like compounds with no toxicity.Communicated by Ramaswamy H. Sarma.

Shape-based Machine Learning Models for the Potential Novel COVID-19 Protease Inhibitors Assisted by Molecular Dynamics Simulation.

BACKGROUND: The vast geographical expansion of novel coronavirus and an increasing number of COVID-19 affected cases have overwhelmed health and public health services. Artificial Intelligence (AI) and Machine Learning (ML) algorithms have extended their major role in tracking disease patterns, and in identifying possible treatments. OBJECTIVE: This study aims to identify potential COVID-19 protease inhibitors through shape-based Machine Learning assisted by Molecular Docking and Molecular Dynamics simulations. METHODS: 31 Repurposed compounds have been selected targeting the main coronavirus protease (6LU7) and a machine learning approach was employed to generate shape-based molecules starting from the 3D shape to the pharmacophoric features of their seed compound. Ligand-Receptor Docking was performed with Optimized Potential for Liquid Simulations (OPLS) algorithms to identify highaffinity compounds from the list of selected candidates for 6LU7, which were subjected to Molecular Dynamic Simulations followed by ADMET studies and other analyses. RESULTS: Shape-based Machine learning reported remdesivir, valrubicin, aprepitant, and fulvestrant as the best therapeutic agents with the highest affinity for the target protein. Among the best shape-based compounds, a novel compound identified was not indexed in any chemical databases (PubChem, Zinc, or ChEMBL). Hence, the novel compound was named 'nCorv-EMBS'. Further, toxicity analysis showed nCorv-EMBS to be suitable for further consideration as the main protease inhibitor in COVID-19. CONCLUSION: Effective ACE-II, GAK, AAK1, and protease 3C blockers can serve as a novel therapeutic approach to block the binding and attachment of the main COVID-19 protease (PDB ID: 6LU7) to the host cell and thus inhibit the infection at AT2 receptors in the lung. The novel compound nCorv- EMBS herein proposed stands as a promising inhibitor to be evaluated further for COVID-19 treatment.

Bacterial protein azurin and derived peptides as potential anti-SARS-CoV-2 agents: insights from molecular docking and molecular dynamics simulations.

The current pandemic SARS-CoV-2 has wreaked havoc in the world, and neither drugs nor vaccine is available for the treatment of this disease. Thus, there is an immediate need for novel therapeutics that can combat this deadly infection. In this study, we report the therapeutic assessment of azurin and its peptides: p18 and p28 against the viral structural S-protein and non-structural 3CLpro and PLpro proteins. Among the analyzed complexes, azurin docked relatively well with the S2 domain of S-protein compared to the other viral proteins. The derived peptide p18 bound to the active site domain of the PLpro protein; however, in other complexes, lesser interactions were recorded. The second azurin derived peptide p28, fared the best among the docked proteins. p28 interacted with all the three viral proteins and the host ACE-2 receptor by forming several electrostatic and hydrogen bonds with the S-protein, 3CLpro, and PLpro. MD simulations indicated that p28 exhibited a strong affinity to S-protein and ACE-2 receptor, indicating a possibility of p28 as a protein-protein interaction inhibitor. Our data suggest that the p28 has potential as an anti-SARS-CoV-2 agent and can be further exploited to establish its validity in the treatment of current and future SARS-CoV crisis.Communicated by Ramaswamy H. Sarma.