scholarly journals Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2

2020 ◽  
Author(s):  
Althaf Shaik ◽  
Nalini Natarajan ◽  
Sivapriya Kirubakaran ◽  
Vijay Thiruvenkatam
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Computational Approach ◽  
Important Target ◽  
Structure Solution ◽  
Wet Lab ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

<p>This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. </p><p></p>We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."

scholarly journals Virtual Screening of FDA Approved Drugs Against Nsp15 Endoribonuclease from SARS CoV-2

2020 ◽  
Author(s):  
Althaf Shaik ◽  
Nalini Natarajan ◽  
Sivapriya Kirubakaran ◽  
Vijay Thiruvenkatam
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Computational Approach ◽  
Important Target ◽  
Structure Solution ◽  
Wet Lab ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

<p>This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. </p><p></p>We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."

Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CLpro: a study by applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking

2022 ◽  
Vol 19 ◽  
Author(s):  
Igor José dos Santos Nascimento ◽  
Thiago Mendonça de Aquino ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
In Silico ◽  
Structural Integrity ◽  
Inhibition Mechanism ◽  
Zinc Database ◽  
Covalent Docking ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential. Method: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM -PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds Result: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the protein's structural integrity, as evidenced by the RMSD, RMSF, Rg, SASA graphics. They also showed interactions with the catalytic dyad (His41 and Cys145) and other essential residues for activity (Glu166 and Gln189) and high affinity for MM-PBSA, with possible covalent inhibition mechanism. Conclution: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafirlukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.

scholarly journals Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

2021 ◽  
Vol 15 (1) ◽  
pp. 8
Author(s):  
Luis Córdova-Bahena ◽  
Axel A. Sánchez-Álvarez ◽  
Angel J. Ruiz-Moreno ◽  
Marco A. Velasco-Velázquez
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Noncovalent Interactions ◽  
Antineoplastic Agent ◽  
Pharmacophore Model ◽  
Hiv Infections ◽  
Binding Behavior ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.

scholarly journals Virtual Screening of an FDA Approved Drugs Database on Two COVID-19 Coronavirus Proteins

2020 ◽  
Author(s):  
Alessandro Contini
Keyword(s):  
Crystal Structure ◽  
Virtual Screening ◽  
Protease Inhibitors ◽  
Virus Replication ◽  
World Wide ◽  
Hiv Infections ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Homology Models

<div>The infection by the 2019-nCoV coronavirus (COVID-19) is a world-wide emergency.</div><div>The crystal structure of a protein essential for virus replication has been filed in the Protein Data</div><div>Bank recently. Additionally, homology models of 24 COVID-19 proteins were made available by</div><div>the Zhang group. In this paper, we present results deriving from the virtual screening of a database</div><div>of more than 3000 FDA approved drugs on two distinct targets. Results showed that some of the</div><div>known protease inhibitors currently used in HIV infections might be helpful for the therapy of</div><div>COVID-19 also.</div>

scholarly journals Virtual Screening of an FDA Approved Drugs Database on Two COVID-19 Coronavirus Proteins

2020 ◽  
Author(s):  
Alessandro Contini
Keyword(s):  
Crystal Structure ◽  
Virtual Screening ◽  
Protease Inhibitors ◽  
Virus Replication ◽  
World Wide ◽  
Hiv Infections ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Homology Models

<div>The infection by the 2019-nCoV coronavirus (COVID-19) is a world-wide emergency.</div><div>The crystal structure of a protein essential for virus replication has been filed in the Protein Data</div><div>Bank recently. Additionally, homology models of 24 COVID-19 proteins were made available by</div><div>the Zhang group. In this paper, we present results deriving from the virtual screening of a database</div><div>of more than 3000 FDA approved drugs on two distinct targets. Results showed that some of the</div><div>known protease inhibitors currently used in HIV infections might be helpful for the therapy of</div><div>COVID-19 also.</div>

scholarly journals Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 734
Author(s):  
Aija Trimdale ◽  
Anatoly Mishnev ◽  
Agris Bērziņš
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Structure Analysis ◽  
Crystal Structure Analysis ◽  
Molecular Association ◽  
Hydroxyl Groups ◽  
Solid Phases ◽  
Solvent Molecules ◽  
Dynamics Simulations

The arrangement of hydroxyl groups in the benzene ring has a significant effect on the propensity of dihydroxybenzoic acids (diOHBAs) to form different solid phases when crystallized from solution. All six diOHBAs were categorized into distinctive groups according to the solid phases obtained when crystallized from selected solvents. A combined study using crystal structure and molecule electrostatic potential surface analysis, as well as an exploration of molecular association in solution using spectroscopic methods and molecular dynamics simulations were used to determine the possible mechanism of how the location of the phenolic hydroxyl groups affect the diversity of solid phases formed by the diOHBAs. The crystal structure analysis showed that classical carboxylic acid homodimers and ring-like hydrogen bond motifs consisting of six diOHBA molecules are prominently present in almost all analyzed crystal structures. Both experimental spectroscopic investigations and molecular dynamics simulations indicated that the extent of intramolecular bonding between carboxyl and hydroxyl groups in solution has the most significant impact on the solid phases formed by the diOHBAs. Additionally, the extent of hydrogen bonding with solvent molecules and the mean lifetime of solute–solvent associates formed by diOHBAs and 2-propanol were also investigated.

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