Spike protein recognizer receptor ACE2 targeted identification of potential natural antiviral drug candidates against SARS-CoV-2

Autor: Zulkar Nain, Mohaimenul Islam Tareq, Abdullah-Al-Mamun, Suza Mohammad Nur, Thamer A. Bouback, Raihan Rahman Imon, Ishtiaq Qadri, Shahedur Rahman, Foysal Ahammad, Saddam Hossen, Rahat Alam, Tomasz M. Karpiński, Abdus Samad, Enamul Kabir Talukder, Sushil Pokhrel
Rok vydání: 2021
Předmět:
RO5
rule of five
MERS
Middle East Respiratory Syndrome
PBVS
pharmacophore based virtual screening
Drug Evaluation
Preclinical
ACE2
Ligands
Biochemistry
Chemical synthesis
COVID-2019
RMSD
root mean square deviation
Molecular dynamics
HTS
High Throughput Screening
AA
amino acids
Structural Biology
COVID-19
coronavirus disease 2019
chemistry.chemical_classification
MM/GBSA
+ssRNA
positive single strand RNA
General Medicine
3D
three dimensional
MD
molecular dynamics
Structure-based pharmacophore model
DUDE
Database of Useful Decoys
Molecular Docking Simulation
SB
structure-based
Molecular docking
Spike Glycoprotein
Coronavirus
SBPM
structure-based pharmacophore model
Angiotensin-Converting Enzyme 2
Pharmacophore
Decoy
2D
two dimensional
ADT
Auto Dock Tools
Protein Binding
Virtual screening
medicine.drug_class
Computational biology
Molecular Dynamics Simulation
ACE2
angiotensin-converting enzyme 2
Antiviral Agents
Article
WHO
World Health Organization
RMSF
root mean square fluctuation
Structure-Activity Relationship
PDB
Protein Data Bank
medicine
TMPRSS2
transmembrane protease serine protease 2
Humans
Computer Simulation
Binding site
Molecular Biology
Biological Products
Binding Sites
SARS-CoV-2
ICTV
International Committee on Taxonomy of Viruses
Enzyme
chemistry
SARS-CoV2
sever acute respiratory syndrome coronavirus 2
T.E.S.T.
Toxicity Estimation Software Tool
Antiviral drug
ADMET
absorption
distribution
metabolism
excretion
and toxicity
Zdroj: International Journal of Biological Macromolecules
ISSN: 0141-8130
Popis: Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.
Databáze: OpenAIRE
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