Targeting SARS-CoV-2 with AI- and HPC-enabled Lead Generation: A First Data Release
Argonne National Laboratory（阿贡国家实验室）；University of Chicago（芝加哥大学）；Rutgers University（罗格斯大学）；Brookhaven National Laboratory（布鲁克海文国家实验室）
Yadu Babuji, Ben Blaiszik, Tom Brettin, Kyle Chard, Ryan Chard, Austin Clyde, Ian Foster, Zhi Hong, Shantenu Jha, Zhuozhao Li, Xuefeng Liu, Arvind Ramanathan, Y… 展开作者
Yadu Babuji, Ben Blaiszik, Tom Brettin, Kyle Chard, Ryan Chard, Austin Clyde, Ian Foster, Zhi Hong, Shantenu Jha, Zhuozhao Li, Xuefeng Liu, Arvind Ramanathan, Yi Ren, Nicholaus Saint, Marcus Schwarting, Rick Stevens, Hubertus van Dam, Rick Wagner
Researchers across the globe are seeking to rapidly repurpose existing drugs or discover new drugs to counter the the novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One promising approach is to train machine learning (ML) and artificial intelligence (AI) tools to screen large numbers of small molecules. As a contribution to that effort, we are aggregating numerous small molecules from a variety of sources, using high-performance computing (HPC) to computer diverse properties of those molecules, using the computed properties to train ML/AI models, and then using the resulting models for screening. In this first data release, we make available 23 datasets collected from community sources representing over 4.2 B molecules enriched with pre-computed: 1) molecular fingerprints to aid similarity searches, 2) 2D images of molecules to enable exploration and application of image-based deep learning methods, and 3) 2D and 3D molecular descriptors to speed development of machine learning models. This data release encompasses structural information on the 4.2 B molecules and 60 TB of pre-computed data. Future releases will expand the data to include more detailed molecular simulations, computed models, and other products.
University of Chicago（芝加哥大学）；Argonne National Laboratory（阿贡国家实验室）；Globus
Researchers worldwide are seeking to repurpose existing drugs or discover new drugs to counter the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A promising source of candidates for such studies is molecules that have been reported in the scientific literature to be drug-like in the context of coronavirus research. We report here on a project that leverages both human and artificial intelligence to detect references to drug-like molecules in free text. We engage non-expert humans to create a corpus of labeled text, use this labeled corpus to train a named enti…
During a long-running pandemic a pathogen can mutate, producing new strains with different epidemiological parameters. Existing approaches to epidemic modelling only consider one virus strain. We have developed a modified SEIR model to simulate multiple virus strains within the same population. As a case study, we investigate the potential effects of SARS-CoV-2 strain B.1.1.7 on the city of Moscow. Our analysis indicates a high risk of a new wave of infections in September-October 2021 with up to 35 000 daily infections at peak. We open-source our code and data.
Ton Duc Thang University（孙德胜大学）；ASICLAND（ASICLAND公司）；Sejong University（世宗大学）；Hanoi University of Industry（河内工业大学）；Northeastern University（东北大学）；Deakin University（迪肯大学）
SARS-CoV-2 is colloquially known as COVID-19 that had an initial outbreak in December 2019. The deadly virus has spread across the world, taking part in the global pandemic disease since March 2020. In addition, a recent variant of SARS-CoV-2 named Delta is intractably contagious and responsible for more than four million deaths over the world. Therefore, it is vital to possess a self-testing service of SARS-CoV-2 at home. In this study, we introduce Fruit-CoV, a two-stage vision framework, which is capable of detecting SARS-CoV-2 infections through recorded cough sounds. Specifically, we conv…
Deep Neural Network-Based Prediction of B-Cell Epitopes for SARS-CoV and SARS-CoV-2: Enhancing Vaccine Design through Machine Learning
College of Agronomy and Biotechnology（农学与生物技术学院）；Accounting/Finance Department（会计与金融系）；Southwest University（西南大学）；Heritage Provider Network（遗产提供者网络）；Epocrates（Epocrates公司）；Athenahealth Inc.（雅典娜健康公司）
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is a major concern in coronavirus disease 2019 (COVID-19) prevention and economic reopening. However, rigorous determination of SARS-COV-2 infectivity is essentially impossible owing to its continuous evolution with over 13752 single nucleotide polymorphisms (SNP) variants in six different subtypes. We develop an advanced machine learning algorithm based on the algebraic topology to quantitatively evaluate the binding affinity changes of SARS-CoV-2 spike glycoprotein (S protein) and host angiotensin-converting enzyme 2 (A…
The increasing prevalence of SARS-CoV-2 variants with spike mutations has raised concerns owing to higher transmission rates, disease severity, and escape from neutralizing antibodies. Rapid and accurate detection of SARS-CoV-2 variants provides crucial information concerning the outbreaks of SARS-CoV-2 variants and possible lines of transmission. This information is vital for infection prevention and control. We used a Cas12a-based RT-PCR combined with CRISPR on-site rapid detection system (RT-CORDS) platform to detect the key mutations in SARS-COV-2 variants, such as 69/70 deletion, N501Y, a…
Background: The COVID-19 pandemic clock is ticking and the survival of many of mankind's modern institutions and or survival of many individuals is at stake. There is a need for treatments to significantly reduce the morbidity and mortality of COVID-19. Hence, we delved deep into the SARS-CoV-2 genome, which is the virus that has caused COVID-19. SARS-CoV-2 is from the same family as SARS-CoV in which three small viral RNAs (svRNA) were recently identified; those svRNAs play a significant role in the virus pathogenesis in mice. Contribution: In this paper, we report potential orthologs of thos…
The 2019 novel coronavirus (2019-nCoV) is currently causing a widespread outbreak centered on Hubei province, China and is a major public health concern. Taxonomically 2019-nCoV is closely related to SARS-CoV and SARS-related bat coronaviruses, and it appears to share a common receptor with SARS-CoV (ACE-2). Here, we perform structural modeling of the 2019-nCoV spike glycoprotein. Our data provide support for the similar receptor utilization between 2019-nCoV and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV, we identify an extend…
We examine a pair of graph generative models for the therapeutic design of novel drug candidates targeting SARS-CoV-2 viral proteins. Due to a sense of urgency, we chose well-validated models with unique strengths: an autoencoder that generates molecules with similar structures to a dataset of drugs with anti-SARS activity and a reinforcement learning algorithm that generates highly novel molecules. During generation, we explore optimization toward several design targets to balance druglikeness, synthetic accessability, and anti-SARS activity based on \icfifty. This generative framework\footno…
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected near 5 million people and led to over 0.3 million deaths. Currently, there is no specific anti-SARS-CoV-2 medication. New drug discovery typically takes more than ten years. Drug repositioning becomes one of the most feasible approaches for combating COVID-19. This work curates the largest available experimental dataset for SARS-CoV-2 or SARS-CoV main protease inhibitors. Based on this dataset, we develop validated machine learning models with relatively low root…
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus of beta coronavirus genus originated in Wuhan, China in December 2019, resulted in the pandemic spread of Corona Virus Disease 2019 (COVID-19) worldwide. This genus also contains SARS-CoV (originated in China 2002-2003) and MERS-CoV (found in Saudi Arabia 2012). The nucleotide sequences of SARS-CoV-2 is closer to SARS-CoV (with approximately 80% identity) than to MERS-CoV. Despite these similarities, SARS-CoV-2 has two main features over the other coronaviruses. The first is the high contagious rate and the second is t…
The devastating impact of the COVID-19 pandemic caused by SARS coronavirus 2 (SARS CoV 2) has raised important questions about viral origin, mechanisms of zoonotic transfer to humans, whether companion or commercial animals can act as reservoirs for infection, and why there are large variations in SARS-CoV-2 susceptibilities across animal species. Powerful in silico modelling methods can rapidly generate information on newly emerged pathogens to aid countermeasure development and predict future behaviours. Here we report an in silico structural homology modelling, protein-protein docking, and …
Spike (S) glycoproteins mediate the coronavirus entry into the host cell. The S1 subunit of S-proteins contains the receptor-binding domain (RBD) that is able to recognize different host receptors, highlighting its remarkable capacity to adapt to their hosts along the viral evolution. While RBD in spike proteins is determinant for the virus-receptor interaction, the active residues lie at the receptor-binding motif (RBM), a region located in RBD that plays a fundamental role binding the outer surface of their receptors. Here, we address the hypothesis that SARS-CoV and SARS-CoV-2 strains able …
Smokers being witnessed with the mild adverse clinical symptoms of SARS-CoV-2, the in-silico study is intended to explore the effect of nicotine binding to the soluble angiotensin converting enzyme II (ACE2) receptor with or without SARS-CoV-2 binding. Nicotine established a stable interaction with the conserved amino acid residues: Asp382, Gly405, His378 and Tyr385 through His401 of the soluble ACE2 that seals its interaction with the INS1. Also, nicotine binding has significantly reduced the affinity score of ACE2 with INS1 to -12.6 kcal/mol (versus -15.7 kcal/mol without nicotine) and the i…
Currently, there is no effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness and low similarity with human genes, SARS-CoV-2 main protease (M$^{\text{pro}}$) is one of the most favorable drug targets. However, the current understanding of the molecular mechanism of M$^{\text{pro}}$ inhibition is limited by the lack of reliable binding affinity ranking and prediction of existing structures of M$^{\text{pro}}$-inhibitor complexes. This work integrates mathematics and deep lea…
SARS-CoV-2 is a global challenge due to its ability to spread much faster than SARS-CoV, which was attributed to the mutations in the receptor binding domain (RBD). These mutations enhanced the electrostatic interactions. Recently, a new strain was reported in the UK that includes a mutation (N501Y) in the RBD, that possibly increases the infection rate. Using Molecular Dynamics simulations (MD) and Monte Carlo (MC) sampling, we showed that the N501 mutation enhances the electrostatic interactions due to the formation of a strong hydrogen bond between SARS-CoV-2-T500 and ACE2-D355 near the mut…
The novel coronavirus SARS-CoV-2 has resulted in a global pandemic with worldwide 6-digital infection rates and thousands death tolls daily. Enormeous effords are undertaken to achieve high coverage of immunization in order to reach herd immunity to stop spreading of SARS-CoV-2 infection. Several SARS-CoV-2 vaccines, based either on mRNA, viral vectors, or inactivated SARS-CoV-2 virus have been approved and are being applied worldwide. However, recently increased numbers of normally very rare types of thromboses associated with thrombocytopenia have been reported in particular in the context o…
Here after performing docking and molecular dynamics of various small molecules derived as a secondary metabolite from fungi, we propose Flaviolin to act as potent inhibitor of 3-chymotrypsin (3C) like protease (3CLpro) of noval corona virus SARS-CoV2 responsible for pandemic condition caused by coronavirus disease 2019 (COVID-19).
The outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a worldwide public health crisis. When the SARS-CoV-2 enters the biological fluids in the human body, different types of biomolecules (in particular proteins) may adsorb on its surface and alter its infection ability. Although great efforts have recently been devoted to the interaction of the specific antibodies with the SARS-CoV-2, it still remains largely unknown how the other serum proteins affect the infection of the SARS-CoV-2. In this work, we systemat…
A recent experimental study found that the binding affinity between the cellular receptor human angiotensin converting enzyme 2 (ACE2) and receptor-binding domain (RBD) in spike (S) protein of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than 10-fold higher than that of the original severe acute respiratory syndrome coronavirus (SARS-CoV). However, main-chain structures of the SARS-CoV-2 RBD are almost the same with that of the SARS-CoV RBD. Understanding physical mechanism responsible for the outstanding affinity between the SARS-CoV-2 S and ACE2 is the "urgent c…
Global coronavirus disease pandemic (COVID-19) caused by newly identified SARS- CoV-2 coronavirus continues to claim the lives of thousands of people worldwide. The unavailability of specific medications to treat COVID-19 has led to drug repositioning efforts using various approaches, including computational analyses. Such analyses mostly rely on molecular docking and require the 3D structure of the target protein to be available. In this study, we utilized a set of machine learning algorithms and trained them on a dataset of RNA-dependent RNA polymerase (RdRp) inhibitors to run inference anal…
Computational drug design based on artificial intelligence is an emerging research area. At the time of writing this paper, the world suffers from an outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus replication is via protease inhibition. We propose an evolutionary multi-objective algorithm (EMOA) to design potential protease inhibitors for SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA maximizes the binding of candidate ligands to the protein using the docking tool QuickVina 2, while at the same time taking into account further objectives lik…
The spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global health crisis. The binding affinity of SARS-CoV-2 (in particular the receptor binding domain, RBD) to its receptor angiotensin converting enzyme 2 (ACE2) and the antibodies is of great importance in understanding the infectivity of COVID-19 and evaluating the candidate therapeutic for COVID-19. In this work, we propose a new method based on molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) to accurately calculate the free energy of SARS-CoV…
The coronavirus SARS-CoV-2 remains an extant threat against public health on a global scale. Cell infection begins when the spike protein of SARS-CoV-2 binds with the cell receptor, angiotensin-converting enzyme 2 (ACE2). Here, we address the role of Tetracycline as an inhibitor for the receptor-binding domain (RBD) of the spike protein. Targeted molecular investigation show that Tetracycline binds more favorably to the RBD (-9.40 kcal/mol) compared to Chloroquine (-6.31 kcal/mol) or Doxycycline (-8.08 kcal/mol) and inhibits attachment to ACE2 to a greater degree (binding efficiency of 2.98 $\…
COVID-19 has affected the world tremendously. It is critical that biological experiments and clinical designs are informed by computational approaches for time- and cost-effective solutions. Comparative analyses particularly can play a key role to reveal structural changes in proteins due to mutations, which can lead to behavioural changes, such as the increased binding of the SARS-CoV-2 surface glycoprotein to human ACE2 receptors. The aim of this report is to provide an easy to follow tutorial for biologists and others without delving into different bioinformatics tools. More complex analyse…
The COVID-19 pandemic triggered by SARS-CoV-2 is a worldwide health disaster. Main protease is an attractive drug target among coronaviruses, due to its vital role in processing the polyproteins that are translated from the viral RNA. There is presently no exact drug or treatment for this diseases caused by SARS-CoV-2. In the present study, we report the potential inhibitory activity of some FDA approved drugs against SARS-CoV-2 main protease by molecular docking study to investigate their binding affinity in protease active site. Docking studies revealed that drug Oseltamivir (anti-H1N1 drug)…
The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been heavily invested in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA Polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-…
The present Health Crisis tests the response of modern science and medicine to finding treatment for a new COVID-19 disease. The presentation on the world stage of antivirals such as remdesivir, obeys to the continuous investigation of biologically active molecules with multiple theoretical, computational and experimental tools. Diseases such as COVID:19 remind us that research into active ingredients for therapeutic purposes should cover all available sources, such as plants. In the present work, in silico tools, specifically docking study, were used to evaluate the binding and inhibition cap…
The outbreak of COVID-19 caused by SARS-CoV-2 has rapidly spread worldwide and has caused over 1,400,000 infections and 80,000 deaths. There are currently no drugs or vaccines with proven efficacy for its prevention and little knowledge was known about the pathogenicity mechanism of SARS-CoV-2 infection. Previous studies showed both virus and host-derived MicroRNAs (miRNAs) played crucial roles in the pathology of virus infection. In this study, we use computational approaches to scan the SARS-CoV-2 genome for putative miRNAs and predict the virus miRNA targets on virus and human genome as wel…
Recent events leading to the worldwide pandemic of COVID-19 have demonstrated the effective use of genomic sequencing technologies to establish the genetic sequence of this virus. In contrast, the COVID-19 pandemic has demonstrated the absence of computational approaches to understand the molecular basis of this infection rapidly. Here we present an integrated approach to the study of the nsp1 protein in SARS-CoV-1, which plays an essential role in maintaining the expression of viral proteins and further disabling the host protein expression, also known as the host shutoff mechanism. We presen…
The wide spread of coronavirus disease 2019 (COVID-19) has declared a global health emergency. As one of the most important targets for antibody and drug developments, Spike RBD-ACE2 interface has received extensive attention. Here, using molecular dynamics simulations, we explicitly evaluated the binding energetic features of the RBD-ACE2 complex of both SARS-CoV and SARS-CoV-2 to find the key residues. Although the overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, the difference in binding affinity is as large as -16.35 kcal/mol. Energy decompos…
Covid-19, a serious respiratory complications caused by SARS-CoV-2 has become one of the global threat to human healthcare system. The present study evaluated the possibility of plant originated approved 117 therapeutics against the main protease protein (MPP), RNA-dependent RNA polymerase (RdRp) and spike protein (S) of SARS-CoV-2 including drug surface analysis by using molecular docking through drug repurposing approaches. The molecular interaction study revealed that Rifampin (-16.3 kcal/mol) were topmost inhibitor of MPP where Azobechalcone were found most potent plant therapeutics for bl…
The deadly coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gone out of control globally. Despite much effort by scientists, medical experts, and society in general, the slow progress on drug discovery and antibody therapeutic development, the unknown possible side effects of the existing vaccines, and the high transmission rate of the SARS-CoV-2, remind us of the sad reality that our current understanding of the transmission, infectivity, and evolution of SARS-CoV-2 is unfortunately very limited. The major limitation is th…
SARS-CoV-2 is what has caused the COVID-19 pandemic. Early viral infection is mediated by the SARS-CoV-2 homo-trimeric Spike (S) protein with its receptor binding domains (RBDs) in the receptor-accessible state. We performed molecular dynamics simulation on the S protein with a focus on the function of its N-terminal domains (NTDs). Our study reveals that the NTD acts as a "wedge" and plays a crucial regulatory role in the conformational changes of the S protein. The complete RBD structural transition is allowed only when the neighboring NTD that typically prohibits the RBD's movements as a we…
Accurate and reliable forecasting of emerging dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants enables policymakers and vaccine makers to get prepared for future waves of infections. The last three waves of SARS-CoV-2 infections caused by dominant variants Omicron (BA.1), BA.2, and BA.4/BA.5 were accurately foretold by our artificial intelligence (AI) models built with biophysics, genotyping of viral genomes, experimental data, algebraic topology, and deep learning. Based on newly available experimental data, we analyzed the impacts of all possible viral spike (S)…
3CL-Pro (or M-Pro) is the SARS-CoV-2 main protease, acting as a homodimer, is responsible for the cleavage of the large polyprotein 1ab transcript in proteins acting on viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and the subject of therapeutic interventions, targeting its catalytic domain. A number of drug candidates have been reported, including some natural products. Here, we investigated in silico, through binding and molecular dynamics simulations, the natural product space for the identification of candidates of 3CL-Pro dimerization inhibitor…
A new coronavirus identified as SARS-CoV-2 virus has brought the world to a state of crisis, causing a major pandemic, claiming more than 433,000 lives and instigating major financial damage to the global economy. Despite current efforts, developing safe and effective treatments remains a major challenge. Moreover, new strains of the virus are likely to emerge in the future. To prevent future pandemics, several drugs with various mechanisms of action are required. Drug discovery efforts against the virus fall into two main categories: (a) monoclonal antibodies targeting the spike protein of th…
The mechanism of SARS-CoV-2 evolution and transmission is elusive and its understanding, a prerequisite to forecast emerging variants, is of paramount importance. SARS-CoV-2 evolution is driven by the mechanisms at molecular and organism scales and regulated by the transmission pathways at the population scale. In this review, we show that infectivity-based natural selection was discovered as the mechanism for SARS-CoV-2 evolution and transmission in July 2020. In April 2021, we proved beyond all doubt that such a natural selection via infectivity-based transmission pathway remained the sole m…
Effective, sensitive, and reliable diagnostic reagents are of paramount importance for combating the ongoing coronavirus disease 2019 (COVID-19) pandemic at a time there is no preventive vaccine nor specific drug available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It would be an absolute tragedy if currently used diagnostic reagents are undermined in any manner. Based on the genotyping of 7818 SARS-CoV-2 genome samples collected up to May 1, 2020, we reveal that essentially all of the current COVID-19 diagnostic targets have had mutations. We further show that SARS-CoV-…
Due to SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) being a novel virus, there are currently no known effective antiviral drugs capable of slowing its progress. To accelerate the discovery of potential drug candidates, bioinformatics based in silico drug discovery can be applied as a very robust tool. In the present study, more than 60 antiviral drugs already available on the market, were chosen after literature survey. These can be used in clinical trials for the treatment of COVID-19. In this study, these candidate drugs were ranked based on their potential to interact with t…
Preliminary epidemiologic, phylogenetic and clinical findings suggest that several novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have increased transmissibility and decreased efficacy of several existing vaccines. Four mutations in the receptor-binding domain (RBD) of the spike protein that are reported to contribute to increased transmission. Understanding physical mechanism responsible for the affinity enhancement between the SARS-CoV-2 variants and ACE2 is the "urgent challenge" for developing blockers, vaccines and therapeutic antibodies against the coronaviru…
Coronaviruses are a class of virus responsible of the recent outbreak of Human Severe Acute Respiratory Syndrome. The molecular machinery behind the viral entry and thus infectivity is based on the formation of the complex of virus spike protein with the angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein can trace the path to develop allosteric drugs to weaken the strength of the spike-ACE2 interface and, thus, reduce the viral infectivity. In this work we present results of the application of the Protein Contact Network (PCN) paradigm…
Heparin has been found to have antiviral activity against SARS-CoV-2. Here, by means of sliding window docking, molecular dynamics simulations and biochemical assays, we investigate the binding mode of heparin to the virus spike glycoprotein and the molecular basis for its antiviral activity. The simulations show that heparin binds at long, mostly positively charged patches on the spike, thereby masking the basic residues of the receptor binding domain and of the S1/S2 site. Experiments corroborated the simulation results by showing that heparin inhibits the cleavage of spike by furin by bindi…
The COVID-19 pandemic has presented many challenges that have spurred biotechnological research to address specific problems. Diagnostics is one area where biotechnology has been critical. Diagnostic tests play a vital role in managing a viral threat by facilitating the detection of infected and/or recovered individuals. From the perspective of what information is provided, these tests fall into two major categories, molecular and serological. Molecular diagnostic techniques assay whether a virus is present in a biological sample, thus making it possible to identify individuals who are current…
Objective: Total 186 biologically important phenylpropanoids and polyketides compounds from different Indian medicinal plants and dietary sources were screened to filter potential compounds that bind at the active site of the therapeutic target proteins of SARS-CoV-2. Method: The molecular docking studies were carried out by using the Autodock Vina. The in silico ADMET and drug-likeness properties of the compounds were predicted from SwissADME server. Result: The molecular docking study of the 186 compounds with the therapeutic target proteins (Mpro, PLpro, RdRp, SGp and ACE2) of SARS-CoV-2 re…
A theory on the conformation transition for SARS-CoV-2 spike protein (S) is proposed. The conformation equilibrium between open (up) and closed (down) conformations of receptor binding domain (RBD) of the spike is studied from the first-principle. The conformational state population is deduced from the free energy change in conformation transition of S protein. We demonstrated that the free energy includes two parts, one from the multi-minima of conformational potential and another from the variation of structural elasticity. Both factors are dependent of amino acid mutation. The former is rel…
Since the epidemic began in November 2019, no viable medicine against SARS-CoV-2 has been discovered. The typical medication discovery strategy requires several years of rigorous research and development as well as a significant financial commitment, which is not feasible in the face of the current epidemic. Through molecular docking and dynamic simulation studies, we used the FDA-approved drug mezonavir against the most important viral targets, including spike (S) glycoprotein, Transmembrane serine protease 2 (TMPRSS2), RNA-dependent RNA polymerase (RdRp), Main protease (Mpro), human angioten…
Despite the huge effort to contain the infection, the novel SARS-CoV-2 coronavirus has rapidly become pandemics, mainly due to its extremely high human-to-human transmission capability, and a surprisingly high viral charge of symptom-less people. While the seek of a vaccine is still ongoing, promising results have been obtained with antiviral compounds. In particular, lactoferrin is found to have beneficial effects both in preventing and soothing the infection. Here, we explore the possible molecular mechanisms with which lactoferrin interferes with SARS-CoV-2 cell invasion, preventing attachm…
The SARS-CoV-2 spike (S) protein facilitates viral infection, and has been the focus of many structure determination efforts. Its flexible loop regions are known to be involved in protein binding and may adopt multiple conformations. This paper identifies the S protein loops and studies their conformational variability based on the available Protein Data Bank (PDB) structures. While most loops had essentially one stable conformation, 17 of 44 loop regions were observed to be structurally variable with multiple substantively distinct conformations based on a cluster analysis. Loop modeling meth…
We propose a novel numerical method able to determine efficiently and effectively the relationship of complementarity between portions of proteins surfaces. This innovative and general procedure, based on the representation of the molecular iso-electron density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, that was unfeasible with previous methods. We first tested the method with a large dataset of known protein complexes obtaining an overall area under the ROC curve of 0.76 in the…
The SARS CoV-2 virus emerged at the end of 2019 and rapidly developed several mutated variants, specifically the Delta and Omicron, which demonstrate higher infectivity and escalating infection cases worldwide. The dominant transmission pathway of this virus is via human-to-human contact and aerosols, but another possible route is through contact with surfaces contaminated with SARS-CoV-2, often exhibiting long-period survival. Here we compare the adsorption capacities of the S1 and S2 subunits of the spike (S) protein from the original variant to that of the S1 subunit from the Delta and Omic…
