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1.
J Am Chem Soc ; 144(7): 2905-2920, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1683927

ABSTRACT

Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Cysteine Proteinase Inhibitors/metabolism , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/enzymology , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacokinetics , Vero Cells
2.
Science ; 372(6547): 1169-1175, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1583231

ABSTRACT

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cystathionine gamma-Lyase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydrogen Sulfide/metabolism , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Biofilms , Crystallography, X-Ray , Cystathionine gamma-Lyase/chemistry , Cystathionine gamma-Lyase/genetics , Cystathionine gamma-Lyase/metabolism , Drug Discovery , Drug Resistance, Bacterial , Drug Synergism , Drug Tolerance , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/growth & development , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/enzymology , Staphylococcus aureus/genetics , Staphylococcus aureus/growth & development
3.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1518621

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
4.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1463775

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
5.
Angew Chem Int Ed Engl ; 60(33): 18231-18239, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1303235

ABSTRACT

Protein crystallography (PX) is widely used to drive advanced stages of drug optimization or to discover medicinal chemistry starting points by fragment soaking. However, recent progress in PX could allow for a more integrated role into early drug discovery. Here, we demonstrate for the first time the interplay of high throughput synthesis and high throughput PX. We describe a practical multicomponent reaction approach to acrylamides and -esters from diverse building blocks suitable for mmol scale synthesis on 96-well format and on a high-throughput nanoscale format in a highly automated fashion. High-throughput PX of our libraries efficiently yielded potent covalent inhibitors of the main protease of the COVID-19 causing agent, SARS-CoV-2. Our results demonstrate, that the marriage of in situ HT synthesis of (covalent) libraires and HT PX has the potential to accelerate hit finding and to provide meaningful strategies for medicinal chemistry projects.


Subject(s)
Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Small Molecule Libraries/metabolism , Acrylamides/chemical synthesis , Acrylamides/metabolism , Acrylates/chemical synthesis , Acrylates/metabolism , Catalytic Domain , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Drug Discovery , High-Throughput Screening Assays , Protein Binding , SARS-CoV-2/chemistry , Small Molecule Libraries/chemical synthesis
6.
Angew Chem Int Ed Engl ; 60(35): 19191-19200, 2021 08 23.
Article in English | MEDLINE | ID: covidwho-1279344

ABSTRACT

SARS-CoV-2 contains a positive single-stranded RNA genome of approximately 30 000 nucleotides. Within this genome, 15 RNA elements were identified as conserved between SARS-CoV and SARS-CoV-2. By nuclear magnetic resonance (NMR) spectroscopy, we previously determined that these elements fold independently, in line with data from in vivo and ex-vivo structural probing experiments. These elements contain non-base-paired regions that potentially harbor ligand-binding pockets. Here, we performed an NMR-based screening of a poised fragment library of 768 compounds for binding to these RNAs, employing three different 1 H-based 1D NMR binding assays. The screening identified common as well as RNA-element specific hits. The results allow selection of the most promising of the 15 RNA elements as putative drug targets. Based on the identified hits, we derive key functional units and groups in ligands for effective targeting of the RNA of SARS-CoV-2.


Subject(s)
Genome , RNA, Viral/metabolism , SARS-CoV-2/genetics , Small Molecule Libraries/metabolism , Drug Evaluation, Preclinical , Ligands , Molecular Structure , Nucleic Acid Conformation , Proton Magnetic Resonance Spectroscopy , RNA, Viral/chemistry , Small Molecule Libraries/chemistry
7.
Int J Mol Sci ; 22(12)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1273456

ABSTRACT

Although the approved vaccines are proving to be of utmost importance in containing the Coronavirus disease 2019 (COVID-19) threat, they will hardly be resolutive as new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a single-stranded RNA virus) variants might be insensitive to the immune response they induce. In this scenario, developing an effective therapy is still a dire need. Different targets for therapeutic antibodies and diagnostics have been identified, among which the SARS-CoV-2 spike (S) glycoprotein, particularly its receptor-binding domain, has been defined as crucial. In this context, we aim to focus attention also on the role played by the S N-terminal domain (S1-NTD) in the virus attachment, already recognized as a valuable target for neutralizing antibodies, in particular, building on a cavity mapping indicating the presence of two druggable pockets and on the recent literature hypothesizing the presence of a ganglioside-binding domain. In this perspective, we aim at proposing S1-NTD as a putative target for designing small molecules hopefully able to hamper the SARS-CoV-2 attachment to host cells.


Subject(s)
SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Binding Sites , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , Drug Repositioning , Humans , Molecular Dynamics Simulation , N-Acetylneuraminic Acid/analogs & derivatives , N-Acetylneuraminic Acid/metabolism , N-Acetylneuraminic Acid/pharmacology , N-Acetylneuraminic Acid/therapeutic use , Protein Binding , Protein Domains , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Spike Glycoprotein, Coronavirus/chemistry , Virus Attachment/drug effects
8.
Bioorg Med Chem Lett ; 42: 128067, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1213059

ABSTRACT

The outbreak of coronavirus (CoV) disease 2019 (COVID-19) caused by the severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has turned into a pandemic. The enzyme 3C-like protease (3CLpro) is essential for the maturation of viral polyproteins in SARS-CoV-2 and is therefore regarded as a key drug target for treating the disease. To identify 3CLpro inhibitors that can suppress SARS-CoV-2 replication, we performed a virtual screening of 500,282 compounds in a Korean compound bank. We then subjected the top computational hits to inhibitory assays against 3CLpro in vitro, leading to the identification of a class of non-covalent inhibitors. Among these inhibitors, compound 7 showed an EC50 of 39.89 µM against SARS-CoV-2 and CC50 of 453.5 µM. This study provides candidates for the optimization of potent 3CLpro inhibitors showing antiviral effects against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Small Molecule Libraries/pharmacology , Animals , Antiviral Agents/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Drug Evaluation, Preclinical , Microbial Sensitivity Tests , Molecular Docking Simulation , Protease Inhibitors/metabolism , Protein Binding , Republic of Korea , Small Molecule Libraries/metabolism , Vero Cells
9.
Bioorg Chem ; 111: 104862, 2021 06.
Article in English | MEDLINE | ID: covidwho-1188327

ABSTRACT

For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CLpro, which is critical for viral replication. We employ explicit solvent molecular dynamics simulations of about 150 compounds docked into 3CLpro's binding site and that had emerged as good main protease ligands from our previous in silico screening of over 1.2 million compounds. By incoporating protein dynamics and applying a range of structural descriptors, such as the ability to form specific contacts with the catalytic dyad residues of 3CLpro and the structural fluctuations of the ligands in the binding site, we are able to further refine our compound selection. Fourteen compounds including estradiol shown to be the most promising based on our calculations were procured and screened against recombinant 3CLpro in a fluorescence assay. Eight of these compounds have significant activity in inhibiting the SARS-CoV-2 main protease. Among these are corilagin, a gallotannin, and lurasidone, an antipsychotic drug, which emerged as the most promising natural product and drug, respectively, and might thus be candidates for drug repurposing for the treatment of COVID-19. In addition, we also tested the inhibitory activity of testosterone, and our results reveal testosterone as possessing moderate inhibitory potency against the 3CLpro enzyme, which may thus provide an explanation why older men are more severely affected by COVID-19.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/metabolism , SARS-CoV-2/enzymology , Small Molecule Libraries/metabolism , Antiviral Agents/metabolism , Binding Sites , Coronavirus 3C Proteases/metabolism , Enzyme Assays , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding
11.
J Phys Chem B ; 125(10): 2533-2550, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1114680

ABSTRACT

The novel RNA virus, severe acute respiratory syndrome coronavirus II (SARS-CoV-2), is currently the leading cause of mortality in 2020, having led to over 1.6 million deaths and infecting over 75 million people worldwide by December 2020. While vaccination has started and several clinical trials for a number of vaccines are currently underway, there is a pressing need for a cure for those already infected with the virus. Of particular interest in the design of anti-SARS-CoV-2 therapeutics is the human protein angiotensin converting enzyme II (ACE2) to which this virus adheres before entry into the host cell. The SARS-CoV-2 virion binds to cell-surface bound ACE2 via interactions of the spike protein (s-protein) on the viral surface with ACE2. In this paper, we use all-atom molecular dynamics simulations and binding enthalpy calculations to determine the effect that a bound ACE2 active site inhibitor (MLN-4760) would have on the binding affinity of SARS-CoV-2 s-protein with ACE2. Our analysis indicates that the binding enthalpy could be reduced for s-protein adherence to the active site inhibitor-bound ACE2 protein by as much as 1.48-fold as an upper limit. This weakening of binding strength was observed to be due to the destabilization of the interactions between ACE2 residues Glu-35, Glu-37, Tyr-83, Lys-353, and Arg-393 and the SARS-CoV-2 s-protein receptor binding domain (RBD). The conformational changes were shown to lead to weakening of ACE2 interactions with SARS-CoV-2 s-protein, therefore reducing s-protein binding strength. Further, we observed increased conformational lability of the N-terminal helix and a conformational shift of a significant portion of the ACE2 motifs involved in s-protein binding, which may affect the kinetics of the s-protein binding when the small molecule inhibitor is bound to the ACE2 active site. These observations suggest potential new ways for interfering with the SARS-CoV-2 adhesion by modulating ACE2 conformation through distal active site inhibitor binding.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Protease Inhibitors/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Drug Design , Humans , Hydrogen Bonding , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Thermodynamics
12.
Bioorg Med Chem ; 33: 116040, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1064895

ABSTRACT

The COVID-19 pandemic continues without specific treatment. In this study it is proposed compounds that can be developed as adjuvant / complementary drugs against COVID-19. Through a search for molecular docking, for the development of a new drug using pharmacological compounds targeting the b1 region in neuropilin-1 (NRP1), which is important for the interaction with the S1 region of the S-Protein of SARS-CoV-2, to slow down the infection process of this virus. A molecular docking was performed using almost 500,000 compounds targeted to interact in the region between amino acids (Thr316, Asp320, Ser346, Thr349, and Tyr353) in NRP1 to determine compounds able to hinder the interaction with the S1 region in the S-Protein. In this study, ten compounds are proposed as potential inhibitors between S1 region in the S-Protein of SARS-CoV-2 with the b1 region in NRP1, to develop a new adjuvant / complementary drug against COVID-19, and to hinder the interaction between SARS-CoV-2 and human cells, with a high probability to be safe in humans, validated by web servers for prediction of ADME and toxicity (PreADMET).


Subject(s)
Molecular Docking Simulation , Neuropilin-1/antagonists & inhibitors , Small Molecule Libraries/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Drug Repositioning , Humans , Neuropilin-1/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use
13.
Angew Chem Int Ed Engl ; 60(12): 6799-6806, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-985937

ABSTRACT

Activity-based probes are valuable tools for chemical biology. However, finding probes that specifically target the active site of an enzyme remains a challenging task. Herein, we present a ligand selection strategy that allows to rapidly tailor electrophilic probes to a target of choice and showcase its application for the two cysteine proteases of SARS-CoV-2 as proof of concept. The resulting probes were specific for the active site labeling of 3CLpro and PLpro with sufficient selectivity in a live cell model as well as in the background of a native human proteome. Exploiting the probes as tools for competitive profiling of a natural product library identified salvianolic acid derivatives as promising 3CLpro inhibitors. We anticipate that our ligand selection strategy will be useful to rapidly develop customized probes and discover inhibitors for a wide range of target proteins also beyond corona virus proteases.


Subject(s)
Coronavirus 3C Proteases/chemistry , Coronavirus Papain-Like Proteases/chemistry , Cysteine Proteinase Inhibitors/chemistry , Molecular Probe Techniques , Molecular Probes/chemistry , SARS-CoV-2/enzymology , Small Molecule Libraries/chemistry , Catalytic Domain , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Hep G2 Cells , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Proof of Concept Study , Protein Binding , Small Molecule Libraries/metabolism , Structure-Activity Relationship
14.
Nat Commun ; 11(1): 5047, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-841208

ABSTRACT

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.


Subject(s)
Betacoronavirus/chemistry , Cysteine Endopeptidases/chemistry , Peptide Fragments/chemistry , Viral Nonstructural Proteins/chemistry , Betacoronavirus/enzymology , Binding Sites , Catalytic Domain , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/metabolism , Drug Design , Mass Spectrometry , Models, Molecular , Peptide Fragments/metabolism , Protein Conformation , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Static Electricity , Viral Nonstructural Proteins/metabolism
15.
Proc Natl Acad Sci U S A ; 117(29): 17195-17203, 2020 07 21.
Article in English | MEDLINE | ID: covidwho-624792

ABSTRACT

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.


Subject(s)
Actinobacteria/genetics , Antiviral Agents/pharmacology , Genome, Bacterial , Macrolides/pharmacology , Protein Interaction Domains and Motifs/drug effects , Small Molecule Libraries/pharmacology , Tacrolimus Binding Protein 1A/chemistry , Tacrolimus Binding Protein 1A/metabolism , Actinobacteria/metabolism , Amino Acid Sequence , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Autoantigens/genetics , Autoantigens/metabolism , Calcineurin/genetics , Calcineurin/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Evolution, Molecular , HEK293 Cells , Humans , Macrolides/chemistry , Macrolides/metabolism , Models, Molecular , Protein Conformation , Sequence Homology , Sirolimus/chemistry , Sirolimus/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
16.
Sci Rep ; 10(1): 13093, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-697117

ABSTRACT

A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming stages of drug development. In this study, we screened the PRESTWICK CHEMICAL LIBRARY composed of 1,520 approved drugs in an infected cell-based assay. The robustness of the screen was assessed by the identification of drugs that already demonstrated in vitro antiviral effect against SARS-CoV-2. Thereby, 90 compounds were identified as positive hits from the screen and were grouped according to their chemical composition and their known therapeutic effect. Then EC50 and CC50 were determined for a subset of 15 compounds from a panel of 23 selected drugs covering the different groups. Eleven compounds such as macrolides antibiotics, proton pump inhibitors, antiarrhythmic agents or CNS drugs emerged showing antiviral potency with 2 < EC50 ≤ 20 µM. By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study provides information for the selection of drugs to be further validated in vivo. Disclaimer: This study corresponds to the early stages of antiviral development and the results do not support by themselves the use of the selected drugs to treat SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/physiology , Small Molecule Libraries/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/isolation & purification , COVID-19 , Caco-2 Cells , Cell Survival/drug effects , Chlorocebus aethiops , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Approval , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Vero Cells , Virus Replication/drug effects
17.
Med Chem ; 17(4): 380-395, 2021.
Article in English | MEDLINE | ID: covidwho-688767

ABSTRACT

BACKGROUND: Globally, over 4.3 million laboratory confirmed cases of COVID-19 have been reported from over 105 countries. No FDA approved antiviral is available for the treatment of this infection. Zhavoronkov et al., with their generative chemistry pipeline, have generated structures that can be potential novel drug-like inhibitors for COVID-19, provided they are validated. 3C-like protease (3CLP) is a homodimeric cysteine protease that is present in coronaviruses. Interestingly, 3CLP is 96.1% structurally similar between SARS-CoV and SARS-CoV-2. OBJECTIVE: To evaluate interaction of generated structures with 3CLP of SARS-CoV (RCSB PDB ID: 4MDS). METHODS: Crystal structure of human SARS-CoV with a non-covalent inhibitor with resolution: 1.598 Å was obtained and molecular docking was performed to evaluate the interaction with generated structures. The MM-GBSA and IFD-SP were performed to narrow down to the structures with better binding energy and IFD score. The ADME analysis was performed on top 5 hits and further MD simulation was employed for top 2 hits. RESULTS: In XP docking, IFD-SP and molecular dynamic simulation studies, the top 2 hits 32 and 61 showed interaction with key amino acid residue GLU166. Structure 61, also showed interaction with HIS164. These interactions of generated structure 32 and 61, with GLU166 and HIS164, indicate the binding of the selected drug within the close proximity of 3CLP. In the MD simulation, the protein- ligand complex of 4MDS and structure 61 was found to be more stable for 10ns. CONCLUSION: These identified structures can be further assessed for their antiviral activity to combat SARS-CoV and COVID-19.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Antiviral Agents/metabolism , COVID-19/drug therapy , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , SARS Virus/chemistry , SARS Virus/enzymology , SARS-CoV-2/enzymology , Small Molecule Libraries/metabolism , Structural Homology, Protein , Structure-Activity Relationship , Substrate Specificity , Thermodynamics , User-Computer Interface
18.
ChemMedChem ; 15(20): 1921-1931, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-670488

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread out as a pandemic threat affecting over 2 million people. The infectious process initiates via binding of SARS-CoV-2 Spike (S) glycoprotein to host angiotensin-converting enzyme 2 (ACE2). The interaction is mediated by the receptor-binding domain (RBD) of S glycoprotein, promoting host receptor recognition and binding to ACE2 peptidase domain (PD), thus representing a promising target for therapeutic intervention. Herein, we present a computational study aimed at identifying small molecules potentially able to target RBD. Although targeting PPI remains a challenge in drug discovery, our investigation highlights that interaction between SARS-CoV-2 RBD and ACE2 PD might be prone to small molecule modulation, due to the hydrophilic nature of the bi-molecular recognition process and the presence of druggable hot spots. The fundamental objective is to identify, and provide to the international scientific community, hit molecules potentially suitable to enter the drug discovery process, preclinical validation and development.


Subject(s)
Betacoronavirus/chemistry , Peptidyl-Dipeptidase A/metabolism , Protein Binding/drug effects , Small Molecule Libraries/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2 , Antiviral Agents/metabolism , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/drug therapy , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protein Domains , SARS-CoV-2
19.
Mol Inform ; 39(8): e2000028, 2020 08.
Article in English | MEDLINE | ID: covidwho-6872

ABSTRACT

The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease (Mpro) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates. Recently, our group has developed a novel deep learning platform - Deep Docking (DD) which provides fast prediction of docking scores of Glide (or any other docking program) and, hence, enables structure-based virtual screening of billions of purchasable molecules in a short time. In the current study we applied DD to all 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro protein. The compounds are made publicly available for further characterization and development by scientific community.


Subject(s)
Coronavirus Infections/pathology , Molecular Docking Simulation , Pneumonia, Viral/pathology , Protease Inhibitors/chemistry , Small Molecule Libraries/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Area Under Curve , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus Infections/virology , Drug Discovery , Humans , Hydrogen Bonding , Ligands , Pandemics , Pneumonia, Viral/virology , Protease Inhibitors/metabolism , ROC Curve , SARS-CoV-2 , Small Molecule Libraries/metabolism , Viral Nonstructural Proteins/metabolism
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