TY - JOUR
T1 - Blue biotechnology
T2 - Computational screening of sarcophyton cembranoid diterpenes for sars-cov-2 main protease inhibition
AU - Ibrahim, Mahmoud A.A.
AU - Abdelrahman, Alaa H.M.
AU - Atia, Mohamed A.M.
AU - Mohamed, Tarik A.
AU - Moustafa, Mahmoud F.
AU - Hakami, Abdulrahim R.
AU - Khalifa, Shaden A.M.
AU - Alhumaydhi, Fahad A.
AU - Alrumaihi, Faris
AU - Abidi, Syed Hani
AU - Allemailem, Khaled S.
AU - Efferth, Thomas
AU - Soliman, Mahmoud E.
AU - Paré, Paul W.
AU - El-Seedi, Hesham R.
AU - Hegazy, Mohamed Elamir F.
N1 - Funding Information:
Funding: Mahmoud F. Moustafa extends his appreciation to the Deanship of Scientific Research at King Khalid University for funding this work under grant No. (R.G.P.1/143/42). The computational work was completed with resources supported by the Science and Technology Development Fund, STDF, Egypt, Grants No. 5480 & 7972 (Granted to Ass. Mahmoud A. A. Ibrahim). Mohamed-Elamir F. Hegazy gratefully acknowledges the financial support from Alexander von Humboldt Foundation “Georg Foster Research Fellowship for Experienced Researchers”.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/7
Y1 - 2021/7
N2 - The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ∆Gbinding < −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ∆Gbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to remodulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.
AB - The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ∆Gbinding < −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ∆Gbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to remodulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.
KW - Cembranoid diterpenes metabolites
KW - Genus Sarcophyton
KW - Molecular docking
KW - Molecular dynamics
KW - Reactome
KW - SARS-CoV-2 main protease
UR - http://www.scopus.com/inward/record.url?scp=85111607042&partnerID=8YFLogxK
U2 - 10.3390/md19070391
DO - 10.3390/md19070391
M3 - Article
C2 - 34356816
AN - SCOPUS:85111607042
SN - 1660-3397
VL - 19
JO - Marine Drugs
JF - Marine Drugs
IS - 7
M1 - 391
ER -