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Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives.

Al-Salahi R, Abuelizz HA, Ghabbour HA, El-Dib R, Marzouk M - Chem Cent J (2016)

Bottom Line: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined.Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents.Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451 Saudi Arabia.

ABSTRACT

Background: The persistent appearance of viral strains that causes a resistant viral infection has led to continuous trials for the design and development of novel antiviral compounds. Benzoquinazoline compounds have been reported to exhibit an interesting antiviral activity. This work aims to study and evaluate the antiviral activity of a newly prepared 2-thioxo-benzo[g]quinazolin-4(3H)-one series against herpes simplex (HSV-1 & 2) and coxsackievirus (CVB4).

Methods: The antiviral activity was performed using the MTT assay, in which Vero cells (obtained from the American Type Culture Collection, ATCC) were propagated in fresh Dulbecco's Modified Eagle's Medium (DMEM) and challenged with 10(4) doses of the virus. Thereafter, the cultures were treated simultaneously with two-fold serial dilutions of the tested compound and incubated at 37 °C for 48 h. Molecular docking studies were done on the CVB4 2A proteinase enzyme using Molegro Virtual Docker software.

Results: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined. Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents. Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

Conclusion: The obtained results gave us some useful insights about the characteristic requirements for future trials to build up and design more active and selective antiviral 2-thioxo-benzo[g]quinazolin-4(3H)-one agents.Graphical abstractCompound 24 superimposed with Ribavirin in CV B4 2A Proteinase enzyme (PDB: 1Z8R) active site.

No MeSH data available.


Related in: MedlinePlus

Ribavirin shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site
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Fig2: Ribavirin shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site

Mentions: To investigate the effect of the different variation of the original skeletons, a molecular docking experiment has been done with correlation to CVB4 2A proteinases. CVB4 2A proteinases perform essential roles involving viral polyprotein self-processing and shutting down of host-cell protein synthesis during viral replication. In addition, CVB4 2A proteinases also cleave heart muscle dystrophin, leading to cytoskeletal dysfunction and the symptoms of human-acquired dilated cardiomyopathy [20]. In silico docking experiments were performed for compounds 1–28 against the X-ray crystal structure of Coxsackievirus B4 2A proteinases (Protein Data Bank (PDB): 1Z8R) [20] using Molegro Virtual Docker software. Docking results were then evaluated by the MolDock score function, and hydrogen bond interactions between tested compounds and the target receptor were used for comparison between the tested and reference compounds [21]. Ribavirin (reference drug) forms eleven hydrogen bonds with amino acid residues at the active site: Tyr 89, Asn 19, Glu 88, Gln 95, Asp 39 and Thr 125, and generated a MolDock score of –100.84 (Fig. 2).Fig. 2


Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives.

Al-Salahi R, Abuelizz HA, Ghabbour HA, El-Dib R, Marzouk M - Chem Cent J (2016)

Ribavirin shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837545&req=5

Fig2: Ribavirin shows hydrogen bonds interactions with CVB4 2A Proteinase enzyme (PDB: 1Z8R) active site
Mentions: To investigate the effect of the different variation of the original skeletons, a molecular docking experiment has been done with correlation to CVB4 2A proteinases. CVB4 2A proteinases perform essential roles involving viral polyprotein self-processing and shutting down of host-cell protein synthesis during viral replication. In addition, CVB4 2A proteinases also cleave heart muscle dystrophin, leading to cytoskeletal dysfunction and the symptoms of human-acquired dilated cardiomyopathy [20]. In silico docking experiments were performed for compounds 1–28 against the X-ray crystal structure of Coxsackievirus B4 2A proteinases (Protein Data Bank (PDB): 1Z8R) [20] using Molegro Virtual Docker software. Docking results were then evaluated by the MolDock score function, and hydrogen bond interactions between tested compounds and the target receptor were used for comparison between the tested and reference compounds [21]. Ribavirin (reference drug) forms eleven hydrogen bonds with amino acid residues at the active site: Tyr 89, Asn 19, Glu 88, Gln 95, Asp 39 and Thr 125, and generated a MolDock score of –100.84 (Fig. 2).Fig. 2

Bottom Line: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined.Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents.Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451 Saudi Arabia.

ABSTRACT

Background: The persistent appearance of viral strains that causes a resistant viral infection has led to continuous trials for the design and development of novel antiviral compounds. Benzoquinazoline compounds have been reported to exhibit an interesting antiviral activity. This work aims to study and evaluate the antiviral activity of a newly prepared 2-thioxo-benzo[g]quinazolin-4(3H)-one series against herpes simplex (HSV-1 & 2) and coxsackievirus (CVB4).

Methods: The antiviral activity was performed using the MTT assay, in which Vero cells (obtained from the American Type Culture Collection, ATCC) were propagated in fresh Dulbecco's Modified Eagle's Medium (DMEM) and challenged with 10(4) doses of the virus. Thereafter, the cultures were treated simultaneously with two-fold serial dilutions of the tested compound and incubated at 37 °C for 48 h. Molecular docking studies were done on the CVB4 2A proteinase enzyme using Molegro Virtual Docker software.

Results: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined. Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents. Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

Conclusion: The obtained results gave us some useful insights about the characteristic requirements for future trials to build up and design more active and selective antiviral 2-thioxo-benzo[g]quinazolin-4(3H)-one agents.Graphical abstractCompound 24 superimposed with Ribavirin in CV B4 2A Proteinase enzyme (PDB: 1Z8R) active site.

No MeSH data available.


Related in: MedlinePlus