The novel Wuhan coronavirus known as SARS-CoV-2 has brought almost unprecedented effects for a non-wartime setting, hitting social, economic and health systems hard.~ Being able to bring to bear pharmaceutical interventions to counteract its effects will represent a major turning point in the fight to turn the tides in this ongoing battle.~ Recently, the World's most powerful supercomputer, SUMMIT, was used to identify existing small molecule pharmaceuticals which may have the desired activity against SARS-CoV-2 through a high throughput virtual screening approach. In this communication, we demonstrate how the use of Bayesian optimization can provide a valuable service for the prioritisation of these calculations, leading to the accelerated identification of high-performing candidates, and thus expanding the scope of the utility of HPC systems for time critical screening
The main reasons for the ongoing COVID-19 (coronavirus disease 2019) pandemic are the unavailability of recommended efficacious drugs or vaccines along with the human to human transmission nature of SARS-CoV-2 virus. So, there is urgent need to search appropriate therapeutic approach by repurposing approved drugs. In this communication, molecular docking analyses of two influenza antiviral drugs baloxavir acid (BXA) and baloxavir marboxil (BXM) were performed with the three therapeutic target proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., main protease (Mpro), …
The emergence of COVID-19 has severely compromised the arsenal of antiviral and antibiotic drugs. Drug discovery is a multistep process with a high failure rate, high cost and it takes approximately 10-12 years for the development of new molecules into the clinical candidate. On the other side, drug repurposing also called old drugs for new uses, is an attractive alternative approach for a new application of marketed FDA approved or investigational drugs. In the current pandemic situation raised due to COVID-19, repurposing of existing FDA approved drugs are emerging as the first line of the t…
Hunan University（湖南大学）；Xiangtan University（湘潭大学）；Central South University（中南大学）；University of Illinois at Chicago（伊利诺伊大学芝加哥分校）；Lehigh University（理海大学）；Frederick National Laboratory for Cancer Research（弗雷德里克国家癌症研究实验室）；National Cancer Institute（国家癌症研究所）；Tel Aviv University（特拉维夫大学）；Cleveland Clinic（克利夫兰诊所）；Case Western Reserve University（凯斯西储大学）
Drug development is time-consuming and expensive. Repurposing existing drugs for new therapies is an attractive solution that accelerates drug development at reduced experimental costs, specifically for Coronavirus Disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, comprehensively obtaining and productively integrating available knowledge and big biomedical data to effectively advance deep learning models is still challenging for drug repurposing in other complex diseases. In this review, we introduce guidelines on ho…
The SARS-CoV-2 pandemic has created a global race for a cure. One approach focuses on designing a novel variant of the human angiotensin-converting enzyme 2 (ACE2) that binds more tightly to the SARS-CoV-2 spike protein and diverts it from human cells. Here we formulate a novel protein design framework as a reinforcement learning problem. We generate new designs efficiently through the combination of a fast, biologically-grounded reward function and sequential action-space formulation. The use of Policy Gradients reduces the compute budget needed to reach consistent, high-quality designs by at…
The world has witnessed unprecedented human and economic loss from the COVID-19 disease, caused by the novel coronavirus SARS-CoV-2. Extensive research is being conducted across the globe to identify therapeutic agents against the SARS-CoV-2. Here, we use a powerful and efficient computational strategy by combining machine learning (ML) based models and high-fidelity ensemble docking simulations to enable rapid screening of possible therapeutic molecules (or ligands). Our screening is based on the binding affinity to either the isolated SARS-CoV-2 S-protein at its host receptor region or to th…
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), the respiratory illness responsible for the COVID-19 pandemic. Currently there is no known vaccine or specific antiviral treatment for COVID-19 and so, there is an urgent need for expedite discovery of new therapeutics to combat the disease until a vaccine will be available worldwide. Drug repurposing is a strategy for identifying new uses for approved drugs that has the advantage (over conventional approaches that attempt to develop a drug from scratch) th…
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…
In the drug repurposing approach, the chemically diverse and potentially safe molecules can be explored as therapeutic potential out of those originally targeted indications. However, the intellectual property rights, and competitive over-heating issue from sharing the same drug pipeline information are drawback of the approach. In current paradigm of drug discovery, despite approval of new chemical entity, the finding of a new ring system for drug discovery have stagnated. In addition, there are still rarely used ring systems from FDA approved drug that can be optimized and used for repurposi…
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'-…
Johns Hopkins University School of Medicine（约翰斯·霍普金斯大学医学院）；Sikkim University（锡金大学）；Magna Graecia University（大希腊大学）
The development of therapeutic targets for COVID-19 treatment is based on the understanding of the molecular mechanism of pathogenesis. The identification of genes and proteins involved in the infection mechanism is the key to shed out light into the complex molecular mechanisms. The combined effort of many laboratories distributed throughout the world has produced the accumulation of both protein and genetic interactions. In this work we integrate these available results and we obtain an host protein-protein interaction network composed by 1432 human proteins. We calculate network centrality …
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…
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…
Virtual screening of phytochemicals was performed through molecular docking, simulation, in silico ADMET and drug-likeness prediction to identify the potential hits that can inhibit the effects of SARS-CoV-2. Considering the published literature on medicinal importance, total 154 phytochemicals with analogous structure from limonoids and triterpenoids were selected to search potential inhibitors for the five therapeutic protein targets of SARS-CoV-2, i.e., 3CLpro (main protease), PLpro (papain-like protease), SGp-RBD (spike glycoprotein-receptor binding domain), RdRp (RNA dependent RNA polymer…
A molecule of dimension 125nm has caused around 479 Million human infections (80M for the USA) & 6.1 Million human deaths (977,000 for the USA) worldwide and slashed the global economy by US$ 8.5 Trillion over two years. The only other events in recent history that caused comparative human life loss through direct usage (either by (wo)man or nature, respectively) of structure-property relations of 'nano-structures' (either (wo)man-made or nature, respectively) were nuclear bomb attacks of Japanese cities by the USA during World War II and 1918 Flu Pandemic. This molecule is SARS-CoV-2, which c…
There remains an urgent need to identify existing drugs that might be suitable for treating patients suffering from COVID-19 infection. Drugs rarely act at a single molecular target, with off target effects often being responsible for undesirable side effects and sometimes, beneficial synergy between targets for a specific illness. Off target activities have also led to blockbuster drugs in some cases, e.g. Viagra for erectile dysfunction and Minoxidil for male pattern hair loss. Drugs already in use or in clinical trials plus approved natural products constitute a rich resource for discovery …
Under the global health emergency caused by coronavirus disease 2019 (COVID-19), efficient and specific therapies are urgently needed. Compared with traditional small-molecular drugs, antibody therapies are relatively easy to develop and as specific as vaccines in targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and thus attract much attention in the past few months. This work reviews seven existing antibodies for SARS-CoV-2 spike (S) protein with three-dimensional (3D) structures deposited in the Protein Data Bank. Five antibody structures associated with SARS-CoV are e…
2019-nCoV is a novel coronavirus was isolated and identified in 2019 in Wuhan, China. On 17th February and according to world health organization, a number of 71 429 confirmed cases worldwide, among them 2162 new cases recorded in the last 24 hours. There is no drug or vaccine for human and animal coronavirus. The inhibition of 3CL hydrolase enzyme provides a promising therapeutic principle for developing treatments against CoViD-19. The 3CLpro (Mpro) known for involving in counteracting the host innate immune response. This work presents the inhibitory effect of some natural compounds against…
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…
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…
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-…
Coronavirus (COVID-19) outbreak in late 2019 and 2020 comprises a serious and more likely a pandemic threat worldwide. Given that the disease has not approved vaccines or drugs up to now, any efforts for drug design and or clinical trails of old drugs based on their mechanism of action are worthy and creditable in such circumstances. Experienced docking experiments using the newly released coordinate structure for COVID-19 protease as a receptor and thoughtfully selected chemicals among antiviral and antibiotics drugs as ligands may be leading in this context. We selected nine drugs from HIV-1…
Pakistan Institute of Engineering & Applied Sciences（巴基斯坦工程与应用科学研究所）
SARS-COV-2 is a positive single-strand RNA-based macromolecule that has caused the death of more than 6.3 million people since June 2022. Moreover, by disturbing global supply chains through lockdown, the virus has indirectly caused devastating damage to the global economy. It is vital to design and develop drugs for this virus and its various variants. In this paper, we developed an in-silico study-based hybrid framework to repurpose existing therapeutic agents in finding drug-like bioactive molecules that would cure Covid-19. We employed the Lipinski rules on the retrieved molecules from the…
There is no vaccine or specific antiviral treatment for COVID-19. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. It is therefore challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze …
Presently, India bears amongst the highest burden of non-communicable diseases such as diabetes mellitus (DM), hypertension (HT), and cardio vascular disease (CVD) and thus represents a vulnerable target to the SARS-CoV-2/COVID-19 pandemic. Involvement of the angiotensin converting enzyme 2 (ACE2) in susceptibility to infection and pathogenesis by SARS-CoV-2 is currently an actively pursued research area. An increased susceptibility to infection in individuals with DM, HT and CVD together with higher levels of circulating ACE2 in these settings presents a scenario where interaction with solubl…
The steep climbing of victims caused by the new coronavirus disease 2019 (COVID-19) throughout the planet is sparking an unprecedented effort to identify effective therapeutic regimens to tackle the pandemic. The SARS-CoV-2 virus is known to gain entry into various cell types through the binding of one of its surface proteins (spike) to the host Angiotensin-Converting Enzyme 2 (ACE2). Thus, spike-ACE2 interaction represents a major target for vaccines and antiviral drugs. A novel method has been recently described by some of the authors to pharmacologically downregulate the expression of targe…
The recent appearance of COVID-19 virus has created a global crisis due to unavailability of any vaccine or drug that can effectively and deterministically work against it. Naturally, different possibilities (including herbal medicines having known therapeutic significance) have been explored by the scientists. The systematic scientific study (beginning with in silico study) of herbal medicines in particular and any drug in general is now possible as the structural components (proteins) of COVID-19 are already characterized. The main protease of COVID-19 virus is $\rm{M^{pro}}$ or $\rm{3CL^{pr…
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…
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…
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…
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…
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…
Proteins can exhibit dynamic structural flexibility as they carry out their functions, especially in binding regions that interact with other molecules. For the key SARS-CoV-2 spike protein that facilitates COVID-19 infection, studies have previously identified several such highly flexible regions with therapeutic importance. However, protein structures available from the Protein Data Bank are presented as static snapshots that may not adequately depict this flexibility, and furthermore these cannot keep pace with new mutations and variants. In this paper we present a sequential Monte Carlo me…
The Coronavirus Disease (COVID-19) pandemic caused by the SARS-coronavirus 2 (SARS-CoV-2) urgently calls for the design of drugs directed against this new virus. Given its essential role in proteolytic processing, the main protease Mpro has been identified as an attractive candidate for drugs against SARS-CoV-2 and similar coronaviruses. Recent high-throughput screening studies have identified a set of existing, small-molecule drugs as potent Mpro inhibitors. Amongst these, Ebselen (2-Phenyl-1,2-benzoselenazol-3-one), a glutathione peroxidase mimetic seleno-organic compound, is particularly at…
School of Software, Shandong University（山东大学软件学院）；Joint SDU-NTU Centre for Artificial Intelligence Research (C-FAIR), Shandong University（山东大学-南洋理工大学人工智能联合研究中心（C-FAIR））；College of Intelligence and Computing, Tianjin University（天津大学智能与计算学部）
In this work, we propose MEDICO, a Multi-viEw Deep generative model for molecule generation, structural optimization, and the SARS-CoV-2 Inhibitor disCOvery. To the best of our knowledge, MEDICO is the first-of-this-kind graph generative model that can generate molecular graphs similar to the structure of targeted molecules, with a multi-view representation learning framework to sufficiently and adaptively learn comprehensive structural semantics from targeted molecular topology and geometry. We show that our MEDICO significantly outperforms the state-of-the-art methods in generating valid, un…
The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spurred unprecedented and concerted worldwide research to curtail and eradicate this pathogen. SARS-CoV-2 has four structural proteins: Envelope (E), Membrane (M), Nucleocapsid (N), and Spike (S), which self-assemble along with its RNA into the infectious virus by budding from intracellular lipid membranes. In this paper, we develop a model to explore the mechanisms of RNA condensation by structural proteins, protein oligomerization and cellular membrane-protein interactions that control the bu…
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…
