In search of SARS CoV-2 replication inhibitors: Virtual screening, molecular dynamics simulations and ADMET analysis

Autor: Normi D. Gajjar, Tejas M. Dhameliya, Prinsa R. Nagar
Rok vydání: 2021
Předmět:
RdRp
NSPs
non-structural proteins
Molecular model
BBB
blood-brain barrier
In silico
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
LOAEL
oral rat chronic toxicity
Druggability
RNA-dependent RNA polymerase
SARS CoV-2
FDA
food and drugs administration
Computational biology
medicine.disease_cause
ssRNA
single stranded ribonucleic acid
Article
Analytical Chemistry
Autodock vina
Inorganic Chemistry
E
envelope protein
RdRp
RNA dependent RNA polymerase
BOILED
brain or intestinal estimated permeation method
medicine
HBD
hydrogen bond donor
Spectroscopy
Coronavirus
Virtual screening
MD simulations
ACE2
angiotensin converting enzyme 2
S
spike glycoprotein
Chemistry
Organic Chemistry
COVID-19
ADMET assay
ADMET
absorption
distribution
metabolism
excretion and toxicity
COVID-19
corona virus disease 2019
MD
molecular dynamics
N
nucleocapsid protein
UTR
untranslated region
HERG
human ether-a-go-go-related gene
M
membrane protein
HBA
hydrogen bond acceptor
Molecular docking
WHO
world health organization
pp1a/b
polyproteins
SARS CoV-2
severe acute respiratory syndrome 2
Zdroj: Journal of Molecular Structure
ISSN: 0022-2860
Popis: Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic in silico virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (2–22) with better binding energy than remdesivir (1), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits (2 and 3) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.
Graphical abstract Image, graphical abstract
Databáze: OpenAIRE
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