scholarly journals AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2

2020 ◽  
Author(s):  
Bowen Tang ◽  
Fengming He ◽  
Dongpeng Liu ◽  
Meijuan Fang ◽  
Zhen Wu ◽  
...  
Keyword(s):  
Drug Design ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Lead Compounds ◽  
Main Protease ◽  
New Chemical Entities ◽  
Covalent Inhibitors ◽  
Key Enzyme ◽  
Approved Drugs ◽  
Aided Design

AbstractThe focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https://github.com/tbwxmu/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.

scholarly journals New Potential Drug Candidates Against SARS-CoV-2 Using Generative Model

2021 ◽  
Author(s):  
Madhusudan Verma
Keyword(s):  
Potential Drug ◽  
Q Learning ◽  
Learning Network ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Variational Autoencoder ◽  
New Chemical Entities ◽  
Key Enzyme ◽  
Approved Drugs

<div>Since known approved drugs like liponavir and ritonavir failed to cure SARS-CoV-2 </div><div>infected patients, it is high time to generate new chemical entities against this virus. </div><div>3CL main protease acts as key enzyme for the growth of a virus which acts as </div><div>biocatalyst and helps to break protein and ultimately in the growth of coronavirus. </div><div>Based on a recently solved structure (PDB ID: 6LU7), we developed a novel </div><div>advanced deep Q-learning network with the fragment-based drug design </div><div>(ADQN-FBDD) along with variational autoencoder with KL annealing and circular </div><div>annealing for generating potential lead compounds targeting SARS-CoV-2 3CLpro. </div><div>Structure-based optimization policy (SBOP) is used in reinforcement learning. The </div><div>reason for using variational autoencoders is that it does not deviate much from actual </div><div>inhibitors, but since VAE suffers from KL diminishing we have used KL annealing </div><div>and circular annealing to address this issue. Researchers can use this compound as </div><div>potential drugs against SARS-CoV-2</div>

scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

scholarly journals A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV-2 main protease

2020 ◽  
Author(s):  
Jeremy D. Baker ◽  
Rikki L. Uhrich ◽  
Gerald C. Kraemer ◽  
Jason E. Love ◽  
Brian C. Kraemer
Keyword(s):  
Hepatitis C ◽  
Drug Development ◽  
Large Scale ◽  
Previous History ◽  
Antiviral Drug ◽  
Case Fatality ◽  
Drug Repurposing ◽  
Main Protease ◽  
Approved Drugs

AbstractThe SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic 1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly. The overall case fatality rate for COVID-19 is estimated to be ∼2.3% overall 3 and 32.3% in hospitalized patients age 70-79 years 4. Therapeutic options for treating the underlying viremia in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ∼6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found ∼50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 μM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including Boceprevir (IC50=0.95 μM), Ciluprevir (20.77μM). Narlaprevir (IC50=1.10μM), and Telaprevir (15.25μM). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.

scholarly journals Potential Binding Efficiency of Antiviral Drug Lopinavir Targeted to the Catalytic Dyad, His41 - Cys145 of SARS CoV -2 Main Protease

2020 ◽  
Author(s):  
Muthu Raj S ◽  
Manohar M ◽  
Mohan M ◽  
Ganesh P ◽  
Marimuthu K
Keyword(s):  
Antiviral Drug ◽  
Emergency Situation ◽  
Viral Disease ◽  
New Drugs ◽  
Viral Population ◽  
Protease Inhibition ◽  
Main Protease ◽  
Model Drug ◽  
Approved Drugs ◽  
Catalytic Dyad

<p>The spread of SARS CoV 2 across the globe rushed the scientific community to find out the potential inhibitor for controlling the viral disease. The main protease (Mpro) or Chymotrypsin protease (3CLpro) is involved in the cleavage of polyproteins, duplication of intracellular materials and release of nonstructural proteins. Cys-His catalytic dyad is located in the SARS-CoV Mpro which is the substrate-binding site located in domains I and II. There are many approved drugs that have their active protease inhibition capability. The targeting of the active site of the main protease is the better option to fight against the viral population. Lopinavir, ritonavir, Remdesivir and Chloroquine are some of the drug candidates considered to be involved in the treatment of SARS CoV 2 under emergency situation as a trial basis. In the present investigation we used lopinavir as a drug to bind the catalytic dyad His41, Cys145 of main protease. The minimum binding of energy of -11.45 kcal/mol observed with the binding of Cys145 and -10.93 kcal/mol was noted with the residue His41. The inhibition constant was also found to be relevant to the binding efficiency of the drug. This is considered to be a model drug target which is initiating the finding of many new drugs to target the current outbreak created by the virus SARS.CoV - 2.</p>

scholarly journals Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential Anti SARS CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation

2021 ◽  
Vol 22 (17) ◽  
pp. 9427
Author(s):  
Simone Di Micco ◽  
Simona Musella ◽  
Marina Sala ◽  
Maria C. Scala ◽  
Graciela Andrei ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Fast Response ◽  
Main Protease ◽  
Promising Target ◽  
Peptide Derivatives ◽  
Novel Coronavirus ◽  
Derivatives Of

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.

scholarly journals In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

2020 ◽  
Author(s):  
Yogesh Kumar ◽  
Harvijay Singh
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Docking Study ◽  
Docking Studies ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

scholarly journals Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Antiviral Drug ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
A Cell ◽  
Aldehyde Groups ◽  
Clinical Potential

ABSTRACTSARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 μM and 0.04 μM respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 μM and 0.33 μM, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.

scholarly journals COVID19 Approved Drug Repurposing: Pocket Similarity Approach

2020 ◽  
Author(s):  
Mohamed Fadlalla
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Drug Binding Site ◽  
Main Protease ◽  
Major Outbreak ◽  
Target Binding ◽  
Approved Drugs

<p>SARS CoV 2 has spread worldwide and caused a major outbreak of coronavirus disease 2019 (COVID-19). To date, no licensed drug or a vaccine is available against COVID19.</p><p>Starting from all of the resolved SARS CoV2 crystal structures, this study aims to find inhibitors for all of the SARS CoV2 proteins. To achieve this, I used PocketMatch to test the similarity of approved drugs binding sites against all of the binding sites found on SARS CoV 2 proteins. After that docking was used to confirm the results.</p><p>I found drugs that inhibit the main protease, Nsp12 and Nsp3. The discovered drugs are either in clinical trials (Sildenafil, Lopinavir, Ritonavir) or have in vitro antiviral activity (Nelfinavir, Indinavir, Amprenavir, depiqulinum , Gemcitabine, Raltitrexed, Aprepitant, montelukast, Ouabain, Raloxifene) whether against SARS CoV 2 or other viruses. In addition to this, further analysis of pockets revealed a steroidal pocket that might open the door to hypotheses on why the mortality of men is higher than women.</p><p>Many of the in silico repurposing studies test binding of the compound to the target using docking. The significance of this study adds to the similarity between the drug binding site and the target binding site. This takes into consideration the dynamic behaviour of the pocket after ligand binding.</p><div><br></div>

scholarly journals Drug Repurposing and New Therapeutic Strategies for SARS-CoV-2 Disease Using a Novel Molecular Modeling-AI Hybrid Workflow

2020 ◽  
Author(s):  
Scott Bembenek
Keyword(s):  
Molecular Modeling ◽  
Therapeutic Targets ◽  
Drug Repurposing ◽  
Preclinical Research ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Usual Process ◽  
Potential Inhibitors ◽  
Computational Platform

<p>The recent<b> </b>outbreak of the novel coronavirus (SARS-CoV-2) poses a significant challenge to the scientific and medical communities to find immediate treatments. The usual process of identifying viable molecules and transforming them into a safe and effective drug takes 10-15 years, with around 5 years of that time spent in preclinical research and development alone. The fastest strategy is to identify existing drugs or late-stage clinical molecules (originally intended for other therapeutic targets) that already have some level of efficacy. To this end, we tasked our novel molecular modeling-AI hybrid computational platform with finding potential inhibitors of the SARS-CoV-2 main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>). Over 13,000 FDA-approved drugs and clinical candidates (represented by just under 30,000 protomers) were examined. This effort resulted in the identification of several promising molecules. Moreover, it provided insight into key chemical motifs surely to be beneficial in the design of future inhibitors. Finally, it facilitated a unique perspective into other potentially therapeutic targets and pathways for SARS-CoV-2.</p>

scholarly journals Repurposing inhibitors for SARS-CoV2 main protease

2020 ◽  
Author(s):  
Kumar Sharp
Keyword(s):  
Viral Replication ◽  
Active Sites ◽  
Drug Repurposing ◽  
Chemotherapeutic Drugs ◽  
Short Term ◽  
Main Protease ◽  
Potential Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Drug repurposing is a promising field to provide potential short-term acceptable therapy for management of coronavirus till a specific anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Chemotherapeutic drugs and anti-retroviral drugs have shown potential binding as inhibitor. In-vitro and clinical trials required to establish final fact.

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