Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

Augustin, Teresa L.; Hajbabaie, Roxanna; Harper, Matthew T.; Rahman, Taufiq

doi:10.3390/molecules25235501

Cited by 16 publications

(11 citation statements)

References 77 publications

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“…Finally, we hope that this study opens the doors for developing metallodrugs as alternatives in the fight against SARS-CoV-2. This is a topic of current intense interest [ 66 , 67 ], and the well-established abilities of coordination complexes to inhibit different stages of the replicative cycles of several viruses may be a good starting point. Furthermore, we believe that this type of study could be useful for developing more efficient techniques for the reliable detection of SARS-CoV-2, which is also an area of intense research efforts [ [68] , [69] , [70] ], in order to control, prevent and therefore reduce its pathogenic spread.…”

Section: Discussionmentioning

confidence: 99%

A SARS-CoV-2 –human metalloproteome interaction map

Chasapis

Georgiopoulou

Perlepes

et al. 2021

Journal of Inorganic Biochemistry

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The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of whether SARS-CoV-2 is physically associated with human metalloproteins. Recently, high-confidence, experimentally supported protein-protein interactions between SARS-CoV-2 and human proteins were reported. In this work, 58 metalloproteins among these human targets have been identified by a structure-based approach. This study reveals that most human metalloproteins interact with the recently discovered SARS-CoV-2 orf8 protein, whose antibodies are one of the principal markers of SARS-CoV-2 infections. Furthermore, this work provides sufficient evidence to conclude that Zn 2+ plays an important role in the interplay between the novel coronavirus and humans. First, the content of Zn-binding proteins in the involved human metalloproteome is significantly higher than that of the other metal ions. Second, a molecular linkage between the identified human Zn-binding proteome with underlying medical conditions that might increase the risk of severe illness from the SARS-CoV-2 virus has been found. Likely perturbations of host cellular metal homeostasis by SARS-CoV-2 infection are highlighted.

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Section: Discussionmentioning

confidence: 99%

A SARS-CoV-2 –human metalloproteome interaction map

Chasapis

Georgiopoulou

Perlepes

et al. 2021

Journal of Inorganic Biochemistry

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“…Therefore, developing a therapy to effectively treat SARS-CoV-2 infections is still mandatory. In this context, repurposing known drugs and taking advantage of in-silico approaches are the preferred ways to promptly select clinical candidates [ 2 , 3 , 4 , 5 ] within a reasonable timeframe and at acceptable costs. Different examples are available in the literature, mainly based on the application of Virtual Screening (VS) procedures [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Different examples are available in the literature, mainly based on the application of Virtual Screening (VS) procedures [ 6 ]. Of note are research articles that have reported data properly validated by in-silico protocols (e.g., docking calibration) and/or in vitro assays for the identification of: (i) inhibitors of the SARS-CoV-2 main and papain-like proteases [ 3 , 4 , 7 ]; (ii) compounds targeting the receptor-binding domain (RBD) of the spike SARS-CoV-2 protein [ 5 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

More Is Always Better Than One: The N-Terminal Domain of the Spike Protein as Another Emerging Target for Hampering the SARS-CoV-2 Attachment to Host Cells

Gaetano

Capasso

Delre

et al. 2021

IJMS

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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.

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“…SARS-CoV-2 has several important drug targets. These include the main protease (M pro ) [ 27 , 28 ], and the papain-like protease (PL pro ). PL pro ’s name is derived from its structural similarity to papain, an enzyme found in papaya.…”

Section: Introductionmentioning

confidence: 99%

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

2021

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The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.

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Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

Cited by 16 publications

References 77 publications

A SARS-CoV-2 –human metalloproteome interaction map

A SARS-CoV-2 –human metalloproteome interaction map

More Is Always Better Than One: The N-Terminal Domain of the Spike Protein as Another Emerging Target for Hampering the SARS-CoV-2 Attachment to Host Cells

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

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