With cases of the new coronavirus disease 2019 (COVID-19) climbing steeply everywhere from Milan to Manhattan , overwhelming one hospital after another and pushing the global death toll past 49,000(2020-4-3), the sprint to find treatments has dramatically accelerated. Drugs that stop the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could save the lives of severely ill patients, protect health care workers and others at high risk of infection, and reduce the time patients spend in hospital beds.
As a world-renowned supplier of small molecular compounds, TargetMol performed a Swiss-Model Homology Modelling process to generate reliable protein models or 3D protein structures of Spike-RBD, ACE2, Mpro (3CLpro), PLpro, nsp16, X domain, RdRp (nsp12) and nsp15. These protein models provide sufficient information for virtual screening against key proteins of SARS-CoV-2.
In the first round of Surflex-Dock virtual screening, to accelerate virtual screening, the maximum quantity of conformations was reduced from 20 to 10, the maximum quantity of rotatable bonds was decreased from 100 to 50, and the options for pre-dock minimization and post-dock minimization of molecules were omitted. The top 500 conformations were selected according to the docking score for the 2nd round of Surflex docking module screening, while reset the parameters as default. Finally, the top 100 conformations according to docking score were selected for manual screening.
Our last step is to apply manual screening to the top 100 compounds, where these compounds were extracted for further analyzing the interactions between ligand and active site such as hydrogen-bond, electrostatic attraction, hydrophobic effect, π-π stacking, and Cation-π Interaction, etc., and whether the structure of ligand has enough rigidity (especially for protein-protein interaction in RBD-ACE2 system, i.e. rotatable quantity of bonds).
TargetMol Anti-COVID-19 Compound Library
|Anti-COVID-19 Compound Library||We selected a number of compounds that may be effective against the SARS-CoV-2，including Lopinavir/Ritonavir, Hydroxychloroquine sulfate, Favipiravir, etc. We also will keep updating it in response to the newest research progress.||2448|
|3CLpro-Targeted compound library (CADD)||Based on the protein structure of 3CLpro, multiple research papers published identified several drugs having the potential to treat COVID-19 by virtual screening, such as drugs that target PLpro and 3CLpro in other viruses such as HIV drugs, Lopinavir and Ritonavir.||161|
|ACE2-Targeted compound library (CADD)||The prefusion SARS-CoV S1 subunit is structurally organized into four distinct domains: NTD, CTD1, CTD2 and CTD3. Among these, CTD1 is the receptor-binding domain, and one CTD1 in the trimer adopts an “up” conformation as a prerequisite for the binding of SARS-CoV to the cellular receptor angiotensin-converting enzyme 2 (ACE2). Similar observations of a protruding “up” CTD1 have also been reported for MERS-CoV S glycoproteins. Targeting the interaction of S protein RBD and ACE2 is an important therapeutic strategy to block coronavirus from entering host cells.||462|
|RBD-Targeted compound library (CADD)||206|
|nsp16-Targeted compound library (CADD)||Nsp16 provides the viral mRNA with the ability to camouflage and obscure itself from the host cell by catalyzing methylation on m7GpppA-RNA, thus preventing recognition and activation of the host immune response which is essential for successful viral infection. Saquinavir and Lopinavir, two anti-HIV drugs, can inhibit the activity of NSP16 methyltransferase, thereby suppressing the function and replication of the virus.||281|
|PLpro-Targeted compound library (CADD)||Papain-like proteinase (PLpro), encoded in nsp3, is responsible for the cleavages of N-terminus of the replicase polyprotein to release Nsp1, Nsp2 and Nsp3, which is essential for correcting virus replication and antagonizing the host’s innate immunity.||474|
|RdRP-Targeted compound library (CADD)||RdRp is the core component of virus genome replication system, and has been used as a very important drug target in the research of SARS-CoV and MERS-CoV inhibitors. Remdesivir, an effective anti-SARS-CoV-2, is a nucleotide analog inhibitor of RdRp.||464|
|X-Domain-Targeted compound library (CADD)||X domain is a conserved structure of pp1a and becomes a part of nsp3 after pp1a cleaved by a virally encoded cysteine protease, the papain-like protease (PLpro). It is a catalytically active ADP-ribose-1″-phosphatase thought to play a role during synthesis of viral subgenomic RNAs thus can be used for drug screening or design.||463|
|nsp15-Targeted compound library (CADD)||Nsp15 is a nidoviral RNA uridylate-specific endoribonuclease (NendoU) carrying C-terminal catalytic domain belonging to the EndoU family. EndoU enzymes are present in all kingdoms of life, where they play various biological functions associated with RNA processing.||470|
|Anti-COVID-19 compound library (CADD)||In the virtual screening for the above eight targets, we carefully selected products with high scores，these compounds have been widely reported in the literature to have the potential of anti-cancer, anti-bacterial, anti-inflammation, or anti-oxidation activity; or have other potential targets.||362|
Promising Antiviral Agents
Based on the above virtual screening results, and combined with the recent clinical reports, we have also obtained some valuable potential drugs for SARS-CoV-2, which can reduce drug development cycle by using drug relocation strategy.
|Darunavir||Darunavir is an HIV protease inhibitor that is used in the treatment of AIDS and HIV infections.||FDA Approved|
|Remdesivir||Remdesivir is a nucleoside analogue, with effective antiviral activity (EC50 of 74 nM for SARS-CoV and MERS-CoV in HAE cells)||Clinical|
|Camostat mesilate||Camostat is a trypsin-like protease inhibitor and inhibits airway epithelial sodium channel (ENaC) function.||Approved/Preclinical|
|Baricitinib||Baricitinib is an orally bioavailable inhibitor of Janus kinases 1 and 2 (JAK1/2), with potential anti-inflammatory, immunomodulating and antineoplastic activities.||FDA Approved|
|Favipiravir||Favipiravir (T-705), an effective and selective RNA-dependent RNA polymerase inhibitor, are applied to treat influenza virus infections.||Approved/Clinical|
|Ribavirin||Ribavirin is a synthetic nucleoside analog of ribofuranose with activity against hepatitis C virus and other RNA viruses.||FDA Approved|
|Chloroquine diphosphate||Chloroquine is an aminoquinoline antimalarial and also is widely used as an autophagy inhibitor. Chloroquine also is an inhibitor of toll-like receptors (TLRs).||FDA Approved|
|Nitazoxanide||Nitazoxanide is a synthetic benzamide with antiprotozoal activity. Nitazoxanide exerts its antiprotozoal activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase dependent electron transfer reaction.||FDA Approved|
COVID-19 has now been declared a pandemic and new treatments are urgently needed as we enter a phase beyond containment. Scientists are endeavoring to find antivirals specific to the virus. As an expert in drug screening, TargetMol would like to share the virtual screening results with scientists all of the world in drug discovery to fight against this novel coronavirus. You can send your name and organization to email@example.com for the full virtual screening results.
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