EXSCALATE: An Extreme-Scale Virtual Screening Platform for Drug Discovery Targeting Polypharmacology to Fight SARS-CoV-2

The social and economic impact of the COVID-19 pandemic demands a reduction of the time required to find a therapeutic cure. In this paper, we describe the EXSCALATE molecular docking platform capable to scale on an entire modern supercomputer for supporting extreme-scale virtual screening campaigns. Such virtual experiments can provide in short time information on which molecules to consider in the next stages of the drug discovery pipeline, and it is a key asset in case of a pandemic. The EXSCALATE platform has been designed to benefit from heterogeneous computation nodes and to reduce scaling issues. In particular, we maximized the accelerators' usage, minimized the communications between nodes, and aggregated the I/O requests to serve them more efficiently. Moreover, we balanced the computation across the nodes by designing an ad-hoc workflow based on the execution time prediction of each molecule. We deployed the platform on two HPC supercomputers, with a combined computational power of 81 PFLOPS, to evaluate the interaction between 70 billion of small molecules and 15 binding-sites of 12 viral proteins of SARS-CoV-2. The experiment lasted 60 hours and it performed more than one trillion ligand-pocket evaluations, setting a new record on the virtual screening scale.

Year 2022 in review - Chronic pain.

This article presents a selection of interesting basic research, clinical studies, new recommendations, new definitions of pain, a new type of nociplastic pain, and a completely new type of post-covid headache. Only foreign and relevant sources are discussed.Copyright © 2022, Czech Medical Association J.E. Purkyne. All rights reserved.

In silico study to find a potent inhibitor, Vilazodone, to cure COVID-19 using molecular docking

The pandemic caused by the coronavirus SARS-COVID-2 has had devastating impact on the world. It has caused a significant number of deaths across the world. Fast spread and lack of vaccine prompted academia to adopt new, fast and reliable methodologies to design new drugs. A combined approach of direct drug design and indirect drug design has been used for molecular docking. In the study, we found a compound, Vilazodone, with a binding energy of -8.40 kcal/mol. The druglikeness properties of this compound are investigated through SWISS ADMET analysis. In this in-silico study, we confirmed this compound is a potential drug candidate against SARS-CoV-2.However, in-vitro and in-vivo studies are required to prove its efficacy. © 2022 IEEE.

Enveloped virus-like particles as a platform for vaccine development

Vaccination is the most effective approach in preventing and controlling the global public health threat of infectious diseases. Enveloped virus-like particles (eVLPs) offer advantages over other subunit vaccines because of their self-adjuvanting properties. Their optimal size and particulate structure activate antigen-presenting cells. The flexibility in manufacturing, applications, and advantages for preventing or treating disease are highlighted by the vaccine candidates described in this review. Previous preclinical and clinical studies demonstrated the immunogenicity of two eVLP vaccine candidates designed to protect against cytomegalovirus. The expression of viral envelope proteins in the eVLPs induces a robust neutralizing antibody response, which is considered a correlate of protection in many viral infections. VBI has developed two vaccine candidates against SARS CoV2, VBI-2902a, and VBI-2905a. Ongoing clinical development of these vaccine candidates will assess human safety and immunogenicity, after one or two doses in previously vaccinated and unvaccinated, individuals.

SARS-CoV-2 infection: Pathogenesis, Immune Responses, Diagnosis

COVID-19 has emerged as the most alarming infection of the present time instigated by the virus SARS-CoV-2. In spite of advanced research technologies, the exact pathophysiology and treatment of the condition still need to be explored. However, SARS-CoV-2 has several structural and functional similarities that resemble SARS-CoV and MERS-CoV which may be beneficial in exploring the possible treatment and diagnostic strategies for SARS-CoV-2. This review discusses the pathogen phenotype, genotype, replication, pathophysiology, elicited immune response and emerging variants of SARSCoV-2 and their similarities with other similar viruses. SARS-CoV-2 infection is detected by a number of diagnostics techniques, their advantages and limitations are also discussed in detail. The review also focuses on nanotechnology-based easy and fast detection of SARS-CoV-2 infection. Various pathways which might play a vital role during SARS-CoV-2 infection have been elaborately discussed since immune response plays a major role during viral infections.

Bilastine Based Drugs as SARS-CoV-2 Protease Inhibitors: Molecular Docking, Dynamics, and ADMET Related Studies

Bilastine drugs, structurally piperidine-1-carboxylate and sulfonyloxyethyl carboxylate derivatives, have significantly been employed as the medication of second-generation antihistamine drugs, and are used for the treatment of allergic rhinoconjunctivities and urticarial (hives). The bilastine drugs, composed of benzene carboxylate, propanoate, carboxylate, methyl-sulfonate, propanoic acid, butanoic acid, and pentanoic acid derivatives, were investigated through computational tools against SARS-CoV-2. The COVID-19 virus consists of five proteases where the curial function is performed by main proteases (M-pro) and Spike proteases (S-pro). The M-pro and S-pro were selected for calculation of molecular docking by these bilastine drugs which showed higher binding energy (<-6.5 kcal/mol) for both proteases. The main carboxylic acid group in bilastine drugs is found the primary key for a high binding score to show the large binding affinity with M-pro and S-pro, and is highly responsible for forming the hydrogen bond although the various hydrophobic bonds were produced as a weak interaction. For justification, the stability of molecular docked ligand-protein complexes was investigated with molecular dynamics. It showed that the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of all these drugs were below the 0.9 angstrom after residue interaction. Moreover, the HOMO-LUMO gap, hardness, and softness provided full details for their chemical reactivity. In this view, the pharmacokinetics and Lipinski rule were calculated, and all of these molecules had satisfied the Lipinski rule. Finally, using the admetSAR online database, absorption, distribution, metabolism, excretion, and toxicity have been calculated which indicated that these bilastine drugs are non-carcinogenic and less harmful for both aquatic and non-aquatic species. [GRAPHICS]

COVID-19 Global Pandemic Fight by Drugs: A Mini-Review on Hope and Hype

Coronavirus disease 2019 (Covid-19), a serious disease caused by the Severe Acute Res-piratory Syndrome-Corona Virus-2 (SARS-CoV-2), was firstly identified in the city of Wuhan of China in December 2019, which then spread and became a global issue due to its high transmission rate. To date, the outbreak of COVID-19 has resulted in infection to 230,868,745 people and the death of 4,732,669 patients. It has paralyzed the economy of all the countries worldwide. Considering the possible mutations of SARS-CoV-2, the current medical emergency requires a longer time for drug design and vaccine development. Drug repurposing is a promising option for potent therapeutics against the pandemic. The present review encompasses various drugs or appropriate combinations of already FDA-approved antimalarial, antiviral, anticancer, anti-inflammatory, and antibiotic therapeu-tic candidates for use in the clinical trials as a ray of hope against COVID-19. It is expected to deliver better clinical and laboratory outcomes of drugs as a prevention strategy for the eradication of the dis-ease.

DESIGN AND SYNTHESIS OF NEW QUINOLINE LINKED TO PYRANOTRIAZOLOPYRIMIDINES CONJUGATES AS NOVEL TARGETS TO DISCOVER PROMISING ANTI-SARS-COV-2

Simple one-pot synthesis of 2-aminopyranoquinoline-3-carbonitriles 2a-d at room temperature from available 8-hydroxyquinaldine, malononitrile, and substituted aromatic aldehydes was realized. Compounds 2a-d were converted into imino ethers 3a-d, condensed with a series of hydrazide under microwave irradiation to yield novel pyranotriazolopyrimidines fused to quinoline 4a-f. Compound 4c, with a cyanomethyl group, was treated with some salicylic arylaldehydes to give the corresponding new pyranotriazolopyrimidine-chromen hybrids 5a-c in good yields. Finally a new series of arylidenes linked to triazolopyrimidopyrano[3,2-h]quinoline 6a-h were designed and synthesized by the reaction of 4a,c, both bearing a cyanomethyl group, with a series of arylaldehydes. The structures of all the compounds were evidenced by H-1/C-13 NMR, IR, and ESI-HRMS. The present study focuses also to predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 MPpro) and to find in advance whether this protein can be targeted by the compounds 4c, 4f, 5a-c and 6a-h thus synthesized. The docking scores of these compounds were compared to that of the co-crystallized native ligand inhibitor (N3) used as a reference standard. The results showed that all the synthesized compounds (4c, 4f, 5a-c and 6a-h) gave interesting binding scores compared to the N3 inhibitor. It has been found that compounds 4c, 4f, 5a and 5b achieved considerably similar binding scores and modes of interaction than the co-crystallized inhibitor N3 indicating good affinity towards SARS-CoV-2 M-pro Conversely, the derivatives 6h and 5c showed binding energy scores (-8.9 and -8.8 kcal/mol, respectively) higher than the M-pro N3 inhibitor (-7.0 kcal/mol), revealing, in their turn, strong interaction with the target protease. However, their interactions were not entirely comparable to those of reference N3.

An Overview of Antivirals for Treating Lower Respiratory Tract Infections

Covid-19 has resulted in a worldwide epidemic (pandemic) with high morbidity and mortality, which has generated efforts in various areas of research looking for safe and effective treatments to combat the virus that generates this disease: SARS-CoV-2. However, several viruses have been emerged/adapted in the last few decades, also affecting the respiratory system. According to the world health organization (WHO), lower respiratory tract infections (LRTIs) are one of the leading causes of death worldwide, and viruses are playing important roles as the cause of these infections. In contrast to the vast repertoire of antibiotics that exist to treat bacteria-caused LRTIs, there are a very few antivirals approved for the treatment of virus-caused LRTIs, whose approach consists mainly of drug reuse. This minireview deals on the main viral pathogens that cause LRTIs and some of the most relevant antivirals to counter them (available drugs and molecules in research/clinical trials), with concise comments of their mechanism of action.

A potent bispecific nanobody protects hACE2 mice against SARS-CoV-2 infection via intranasal administration.

The dramatically expanding coronavirus disease 2019 (COVID-19) needs multiple effective countermeasures. Neutralizing nanobodies (Nbs) are a potential therapeutic strategy for treating COVID-19. Here, we characterize several receptor binding domain (RBD)-specific Nbs isolated from an Nb library derived from an alpaca immunized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S); among them, three Nbs exhibit picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and circulating SARS-CoV-2 variants. To improve their efficacy, various configurations of Nbs are engineered. Nb15-NbH-Nb15, a trimer constituted of three Nbs, is constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibits single-digit ng/ml neutralization potency against the wild-type and Delta variants of SARS-CoV-2 with a long half-life in vivo. In addition, we show that intranasal administration of Nb15-NbH-Nb15 provides effective protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both the prevention and treatment of SARS-CoV-2 through respiratory administration.

Potent and Persistent Antibody Response in COVID-19 Recovered Patients.

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Virus-specific antibodies can be detected in infected patients approximately two weeks after symptom onset. In this study, we set up ELISA technology coating with purified SARS-CoV-2 S and N proteins to study the antibody response of 484 serum samples. We established a surrogate viral inhibition assay using SARS-CoV-2 S protein pseudovirus system to determine the neutralization potency of collected serum samples. Here, we report robust antibody responses to SARS-CoV-2 in 484 recovered patients varying from 154 to 193 days, with 92% of recovered patients displaying a positive virus-specific spike glycoprotein IgG (s-IgG) response, while the ratio of positive spike glycoprotein IgM (s-IgM) reached 63%. Furthermore, moderate to potent neutralization activities were also observed in 62% of patients, correlating significantly with s-IgG response. This study strongly supports the long-term presence of antibodies in recovered patients against SARS-CoV-2, although all serum samples were collected from individuals with mild or moderate symptoms.

Molecular interaction analysis of Sulawesi propolis compounds with SARS-CoV-2 main protease as preliminary study for COVID-19 drug discovery.

Coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health concern, as the World Health Organization declared this outbreak to be a global pandemic in March 2020. The need for an effective treatment is urgent because the development of an effective vaccine may take years given the complexity of the virus and its rapid mutation. One promising treatment target for COVID-19 is SARS-CoV-2 main protease. Thus, this study was aimed to examine whether Sulawesi propolis compounds produced by Tetragonula sapiens inhibit the enzymatic activity of SARS-CoV-2 main protease. In this study, molecular docking was performed to analyze the interaction profiles of propolis compounds with SARS-CoV-2 main protease. The results illustrated that two compounds, namely glyasperin A and broussoflavonol F, are potential drug candidates for COVID-19 based on their binding affinity of -7.8 kcal/mol and their ability to interact with His41 and Cys145 as catalytic sites. Both compounds also displayed favorable interaction profiles with SARS-CoV-2 main protease with binding similarities compared to inhibitor 13b as positive control 63% and 75% respectively.

FDA recommended potent drugs against COVID-19: Insight through molecular docking.

Human Coronavirus (COVID-19) is a worldwide pandemic of 2019-20 that was emerged in China in December 2019. More than 37,000deaths with7, 84, 440confirmed cases has been reported from around 200 different countries has been reported till now and the number is increasing every second. The spread is said to be through human to human transmission via close contact or respiratory droplets produced when people cough or sneeze. No treatment for the illness has been approved yet. The urgent need is to find solution to this growing problem that has affected the whole mankind. World Health Organisation (WHO) as well as US Food and Drug Administration (FDA) are continuously working to find the solution. In the same line they have proposed many potent drugs that may have efficiency against the newly emerged viral infection. To support the efforts the present study is designed to carry out the in silico analysis viz. Docking studies of around 16drugs recently recommended by US FDA by observing the interaction of test molecules with SARS proteinase.

Evaluating the potency of Sulawesi propolis compounds as ACE-2 inhibitors through molecular docking for COVID-19 drug discovery preliminary study.

Coronavirus disease (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Up to date, there has been no specific cure to treat the disease. Indonesia is one of the countries that is still fighting to control virus transmission. Yet, at the same time, Indonesia has a rich biodiversity of natural medicinal products that potentially become an alternative cure. Thus, this study examined the potency of a natural medicinal product, Sulawesi propolis compounds produced by Tetragonula sapiens, inhibiting angiotensin-converting activity enzyme-2 (ACE-2), a receptor of SARS-CoV-2 in the human body. In this study, molecular docking was done to analyze the docking scores as the representation of binding affinity and the interaction profiles of propolis compounds toward ACE-2. The results illustrated that by considering the docking score and the presence of interaction with targeted sites, five compounds, namely glyasperin A, broussoflavonol F, sulabiroins A, (2S)-5,7-dihydroxy-4'-methoxy-8-prenylflavanone and isorhamnetin are potential to inhibit the binding of ACE-2 and SARS-CoV-2, with the docking score of -10.8, -9.9, -9.5, -9.3 and -9.2 kcal/mol respectively. The docking scores are considered to be more favorable compared to MLN-4760 as a potent inhibitor.