Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

Biomolecules

TarekMohamed Abd El-Aziz¹  JamesD. Stockand¹  EslamB. Elkaeed²  AhmedM. Metwaly³  ReemK. Arafa⁴  Afnan Hassan⁴  Amr El-Demerdash⁵  IbrahimH. Eissa⁶ 

[1] Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA;Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Riyadh, Saudi Arabia;Department of Pharmacognosy & Medicinal Plants, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt;Drug Design and Discovery Lab, Zewail City of Science and Technology, Giza 12578, Egypt;Metabolic Biology & Biological Chemistry Department, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK;Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt;

关键词: virtual screening;    docking;    COVID-19;    antiviral;    cytotoxicity;    guanidine alkaloids;   

DOI  :  10.3390/biom11030460

来源: DOAJ

【 摘 要 】

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (M^pro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against M^pro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD₅₀, rat maximum tolerated dose, rat oral LD₅₀, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

【 授权许可】

Unknown