Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Bolcato, Giovanni; Bissaro, Maicol; Pavan, Matteo; Sturlese, Mattia; Moro, Stefano

doi:10.1038/s41598-020-77700-z

Cited by 48 publications

(35 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Likewise, inspection for these residues revealed that Hit1 targeted hotspot residues His41, Met49, Cys145, Met165, and Gln189, while Hit2 targeted residues His41, Met49, Cys145, His164, Met165, Glu166, and Gln189 characterized by various hydrogen, hydrophobic, and π-alkyl bonds (Figure 4 and Supplementary Table 2). Similarly, a previously established binding mode for Lopinavir and Ritonavir against 3CL pro was obtained during our analysis which provides support for the binding mode of identified Hit compounds (Bolcato et al, 2020;. Recently, a terpenoid (T3) from marine sponge Cacospongia mycofijiensis was also identified through in silico studies against SARS CoV-2 3CL pro showing similar binding interactions like our hit molecules (Sepay et al, 2021).…”

Section: Discussionsupporting

confidence: 84%

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

et al. 2021

View full text Add to dashboard Cite

The rapid spread of COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a worldwide health emergency. Unfortunately, to date, a very small number of remedies have been to be found effective against SARS-CoV-2 infection. Therefore, further research is required to achieve a lasting solution against this deadly disease. Repurposing available drugs and evaluating natural product inhibitors against target proteins of SARS-CoV-2 could be an effective approach to accelerate drug discovery and development. With this strategy in mind, we derived Marine Natural Products (MNP)-based drug-like small molecules and evaluated them against three major target proteins of the SARS-CoV-2 virus replication cycle. A drug-like database from MNP library was generated using Lipinski’s rule of five and ADMET descriptors. A total of 2,033 compounds were obtained and were subsequently subjected to molecular docking with 3CLpro, PLpro, and RdRp. The docking analyses revealed that a total of 14 compounds displayed better docking scores than the reference compounds and have significant molecular interactions with the active site residues of SARS-CoV-2 virus targeted proteins. Furthermore, the stability of docking-derived complexes was analyzed using molecular dynamics simulations and binding free energy calculations. The analyses revealed two hit compounds against each targeted protein displaying stable behavior, binding affinity, and molecular interactions. Our investigation identified two hit compounds against each targeted proteins displaying stable behavior, higher binding affinity and key residual molecular interactions, with good in silico pharmacokinetic properties, therefore can be considered for further in vitro studies.

show abstract

Section: Discussionsupporting

confidence: 84%

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Although they were prescribed ad hoc to reduce SARS-CoV-2 infection, these drugs are no longer used, and they require further clinical evidences to be officially approved. Numerous computational studies showed that these two drugs interact rather well with SARS-CoV-2 M pro [ 50 , 51 ]. Unfortunately, their potency is still not sufficient to determine an adequate reduction of the infection.…”

Section: Sars-cov-2 M Pro Inhibitorsmentioning

confidence: 99%

SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

et al. 2021

View full text Add to dashboard Cite

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO’s main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (Mpro) are becoming more and more promising candidates. Mpro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 Mpro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 Mpro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds.

show abstract

“…Between working with monomeric or dimeric form for the MetaDy studies, we strategically chose the first one. In this regard, we found a precedent in the use of M pro monomers as drug targets, but with different approaches (Bolcato et al., 2020 ). The fact is that there is strong evidence that the active form of Mpros is dimeric, although a monomer-dimer equilibrium coexists (Xiong et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers

Rocha

Chaves

Fischer

et al. 2021

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

The main-protease (M pro ) catalyzes a crucial step for the SARS-CoV-2 life cycle. The recent SARS-CoV-2 presents the main protease (M CoV2 pro ) with 12 mutations compared to SARS-CoV (M CoV1 pro ). Recent studies point out that these subtle differences lead to mobility variances at the active site loops with functional implications. We use metadynamics simulations and a sort of computational analysis to probe the dynamic, pharmacophoric and catalytic environment differences between the monomers of both enzymes. So, we verify how much intrinsic distinctions are preserved in the functional dimer of M CoV2 pro , as well as its implications for ligand accessibility and optimized drug screening. We find a significantly higher accessibility to open binding conformers in the M CoV2 pro monomer compared to M CoV1 pro . A higher hydration propensity for the M CoV2 pro S2 loop with the A46S substitution seems to exercise a key role. Quantum calculations suggest that the wider conformations for M CoV2 pro are less catalytically active in the monomer. However, the statistics for contacts involving the N-finger suggest higher maintenance of this activity at the dimer. Docking analyses suggest that the ability to vary the active site width can be important to improve the access of the ligand to the active site in different ways. So, we carry out a multiconformational virtual screening with different ligand bases. The results point to the importance of taking into account the protein conformational multiplicity for new promissors anti M CoV2 pro ligands. We hope these results will be useful in prospecting, repurposing and/or designing new anti SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma

show abstract

Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir

Cited by 48 publications

References 41 publications

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

Computational Simulations Identified Marine-Derived Natural Bioactive Compounds as Replication Inhibitors of SARS-CoV-2

SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers

Contact Info

Product

Resources

About