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 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 Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Carlos Javier Alméciga-Díaz ◽  
Luisa N. Pimentel-Vera ◽  
Angela Caro ◽  
Angela Mosquera ◽  
Camilo Andrés Castellanos Moreno ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Clinical Information ◽  
Virus Genome ◽  
Pharmacological Agents ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

scholarly journals Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

2020 ◽  
Author(s):  
Lovika Mittal ◽  
Anita Kumari ◽  
Mitul Srivastava ◽  
Mrityunjay Singh ◽  
Shailendra Asthana
Keyword(s):  
Virtual Screening ◽  
Design Method ◽  
Hot Spot ◽  
Drug Repurposing ◽  
Inhibitory Effect ◽  
Drug Molecules ◽  
Main Protease ◽  
Approved Drugs ◽  
Novel Drug

<p>In this work, computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19 main protease (M<sup>pro</sup>)<sup> </sup>. The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 M<sup>pro</sup> to identify potential drug molecules. With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVID-19 M<sup>pro</sup>. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8.0 kcal/mol and MMGBSA > -68.0 kcal/mol. The binding pattern of these compounds suggests that they interacted with key <i>hot-spot</i> residues. Also, their pharmacokinetic annotations and therapeutic importance have indicated that they possess drug-like properties and could pave their way for<i> in-vitro</i> studies. The findings of this work will be significant for structure and pharmacophore-based designing. </p>

scholarly journals Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

2020 ◽  
Author(s):  
Lovika Mittal ◽  
Anita Kumari ◽  
Mitul Srivastava ◽  
Mrityunjay Singh ◽  
Shailendra Asthana
Keyword(s):  
Virtual Screening ◽  
Design Method ◽  
Hot Spot ◽  
Drug Repurposing ◽  
Inhibitory Effect ◽  
Drug Molecules ◽  
Main Protease ◽  
Approved Drugs ◽  
Novel Drug

<p>In this work, Computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19. The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 to identify potential drug molecules.</p> <p>With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVD-19. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8 kcal/mol and MMGBSA > -90 kcal/mol. The binding pattern of these compounds suggests that they interact with key <i>hot-spot</i> residues. Also, the pharmacokinetic annotations and their biological activity have indicated that they possess drug-like properties and pave their way for in vitro studies</p> <p>The findings of this work will be significant for structure and pharmacophore-based designing</p>

scholarly journals Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

2020 ◽  
Author(s):  
Lovika Mittal ◽  
Anita Kumari ◽  
Mitul Srivastava ◽  
Mrityunjay Singh ◽  
Shailendra Asthana
Keyword(s):  
Virtual Screening ◽  
Design Method ◽  
Hot Spot ◽  
Drug Repurposing ◽  
Inhibitory Effect ◽  
Drug Molecules ◽  
Main Protease ◽  
Approved Drugs ◽  
Novel Drug

<p>In this work, computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19 main protease (M<sup>pro</sup>)<sup> </sup>. The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 M<sup>pro</sup> to identify potential drug molecules. With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVID-19 M<sup>pro</sup>. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8.0 kcal/mol and MMGBSA > -68.0 kcal/mol. The binding pattern of these compounds suggests that they interacted with key <i>hot-spot</i> residues. Also, their pharmacokinetic annotations and therapeutic importance have indicated that they possess drug-like properties and could pave their way for<i> in-vitro</i> studies. The findings of this work will be significant for structure and pharmacophore-based designing. </p>

scholarly journals Virtual Screening Based Prediction of Potential Drugs for COVID-19

2020 ◽  
Author(s):  
Sekhar Talluri
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Viral Infections ◽  
Genomic Sequence ◽  
Three Dimensional ◽  
Drug Repurposing ◽  
Dimensional Structure ◽  
Main Protease ◽  
Approved Drugs ◽  
Target Effects

SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using molecular docking based virtual screening of all approved drugs. The results of this study confirm preliminary reports that some of the drugs approved for treatment of other viral infections have the potential for treatment of COVID-19. Selected antiviral drugs, approved for human therapeutic applications, were ranked for potential effectiveness against COVID-19, based on predicted binding energy to the target Mpro of SARS-CoV-2, and novel candidates for drug repurposing were identified in this study. In addition, potential mechanisms for beneficial off target effects of some drugs in clinical trials were identified by using molecular docking.

DOCKING STUDY OF NOVEL N-SUBSTITUTED 2,5-BIS[(7-CHLOROQUINOLIN-4-YL)AMINO]PENTANOIC DERIVATIVES AS SELECTIVE HIGH-BINDER WITH ANGIOTENSIN CONVERTING ENZYME 2

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (08) ◽  
pp. 16-24
Author(s):  
Mohammed Oday Ezzat ◽  
Basma M. Abd Razik ◽  
Kutayba F. Dawood
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Active Site ◽  
Docking Study ◽  
World Health ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pharmaceutical Properties ◽  
Novel Coronavirus

The prevalence of a novel coronavirus (2019-nCoV) in the last few months represents a serious threat as a world health emergency concern. Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor for the respiratory syndrome of coronavirus epidemic in 2019 (2019-nCoV). In this work, the active site of ACE2 is successfully located by Sitmap prediction tool and validated by different marketed drugs. To design and discover new medical countermeasure drugs, we evaluate a total of 184 molecules of 7-chloro-N-methylquinolin-4-amine derivatives for binding affinity inside the crystal structure of ACE2 located active site. A novel series of N-substituted 2,5-bis[(7-chloroquinolin-4-yl)amino]pentanoic acid derivatives is generated and evaluated for a prospect as a lead compound for (2019-nCoV) medication with a docking score range of (-10.60 to -8.99) kcal/mol for the highest twenty derivatives. Moreover, the ADME pharmaceutical properties were evaluated for further proposed experimental evaluation in vitro or in vivo

scholarly journals Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Abhik Kumar Ray ◽  
Parth Sarthi Sen Gupta ◽  
Saroj Kumar Panda ◽  
Satyaranjan Biswal ◽  
Malay Kumar Rana
Keyword(s):  
Virtual Screening ◽  
Binding Energies ◽  
Great Promise ◽  
Main Protease ◽  
Promising Target ◽  
Inhibitory Potential ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>

scholarly journals Evaluation of Yashtimadhu (Glycyrrhiza glabra) active Phytochemicals Against Novel Coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Dharmendra Kumar Maurya
Keyword(s):  
Viral Entry ◽  
Virus Disease ◽  
Scientific Basis ◽  
Docking Studies ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus emerged from Wuhan, China in December 2019. It has spread to more than 205 countries and become pandemic now. Currently, there are no FDA approved drugs or vaccines available and hence several studies are going on in search of suitable drug that can target viral proteins or host receptor for the prevention and management of COVID-19. The search for plant-based anti-viral agents against the SARS-CoV-2 is promising because several of plants have been shown to possess anti-viral activities against different viruses. Here, we used molecular docking approach to explore the use of Indian Ayurvedic herbs, Yashtimadhu in prevention and management of COVID-19. In the present study we have evaluated the effectiveness of phytochemicals found in Yashtimadhu against Main Protease (Mpro), Spike (S) protein and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor and furin protease. Apart from this, we have also performed in-silico drug-likeness and predicted pharmacokinetics of the selected phytochemicals found in the Yashtimadhu. Our study shows that several phytochemicals found in this plant have potential to bind with important proteins of SARS-CoV-2 which are essential for viral infection and replication. Overall our study provides scientific basis in terms of binding of active ingredients present in Yashtimadhu with SARS-CoV-2 target proteins. Our docking studies reveal that Yashtimadhu may inhibit the viral severity by interfering with viral entry as well as its multiplication in the infected persons. Thus Yashtimadhu may be helpful in the prevention and management of the COVID-19.

scholarly journals Potential Inhibitors Against Papain-like Protease of Novel Coronavirus (COVID-19) from FDA Approved Drugs

2020 ◽  
Author(s):  
Rimanshee Arya ◽  
Amit Das ◽  
Vishal Prashar ◽  
Mukesh Kumar
Keyword(s):  
Life Cycle ◽  
Active Site ◽  
Homology Model ◽  
Docking Studies ◽  
Rational Selection ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs ◽  
Selection Of

<p>The cases of 2019 novel coronavirus (COVID-19) infection have been continuously increasing ever since its outbreak in China last December. Currently, there are no approved drugs to treat the infection. In this scenario, there is a need to utilize the existing repertoire of FDA approved drugs to treat the disease. The rational selection of these drugs could be made by testing their ability to inhibit any COVID-19 proteins essential for viral life-cycle. We chose one such crucial viral protein, the papain-like protease (PLpro), to screen the FDA approved drugs <i>in silico</i>. The homology model of the protease was built based on the SARS-coronavirus PLpro structure, and the drugs were docked in S3/S4 pockets of the active site of the enzyme. In our docking studies, fifteen FDA approved drugs, including chloroquine and formoterol, bind the target enzyme with significant affinity and good geometry, suggesting their potential to be utilized against the virus.</p>

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