In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

Alberca, Lucas Nicolás; Chuguransky, Sara; Álvarez, Cecilia; Talevi, Alan; Salas-Sarduy, Emir

doi:10.3389/fchem.2019.00534

Cited by 27 publications

(22 citation statements)

References 113 publications

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“…This specific experimental behavior does not allow a direct comparison with reference compounds, despite the theoretical predictions could suggest a tighter binding. Overall, it is quite hard to show the inhibitory effect by non-covalent inhibitors and the obtainment of non-standard sigmoidal dose-response curve has been already reported, such as for falcipain-2 binders (Alberca et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

In silico Analysis Revealed Potential Anti-SARS-CoV-2 Main Protease Activity by the Zonulin Inhibitor Larazotide Acetate

et al. 2021

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The most severe outcome of COVID-19 infection is the development of interstitial pneumonia causing acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), both responsible for the infected patients' mortality. ALI and ARDS are characterized by a leakage of plasma components into the lungs, compromising their ability to expand and optimally engage in gas exchange with blood, resulting in respiratory failure. We have previously reported that zonulin, a protein dictating epithelial and endothelial permeability in several districts, including the airways, is involved in ALI pathogenesis in mouse models, and that its peptide inhibitor Larazotide acetate (also called AT1001) ameliorated ALI and subsequent mortality by decreasing mucosal permeability to fluid and extravasation of neutrophils into the lungs. With the recent crystallographic resolution of the SARS-CoV-2 main protease (Mpro), an enzyme fundamental in the viral lifecycle, bound to peptidomimetic inhibitors N3 and 13b, we were able to perform molecular modeling investigation showing that AT1001 presents structural motifs similar to co-crystallized ligands. Specifically, molecular docking, MM-GBSA-based predictions and molecular dynamics showed that AT1001 docks extremely well in the Mpro catalytic domain through a global turn conformational arrangement without any unfavorable steric hindrance. Finally, we have observed that AT1001 can be superimposed onto the crystallized structures of N3 and 13b, establishing a higher number of interactions and accordingly a tighter binding. In vitro studies confirmed AT1001 anti-Mpro and preliminary investigation indicted an anti-viral activity. Combined, these studies suggest that AT1001, besides its well-demonstrated effect in ameliorating mucosal permeability in ALI/ARDS, may also exert a direct anti-SARS-CoV-2 effect by blocking the Mpro. AT1001 has been used extensively in a variety of animal models of ALI demonstrating robust safety and efficacy; it is currently in phase 3 trials in celiac subjects showing strong safety and efficacy profiles. We therefore propose its use as a specific anti-SARS-CoV-2 multitargeting treatment for the current pandemic.

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Section: Discussionmentioning

confidence: 99%

In silico Analysis Revealed Potential Anti-SARS-CoV-2 Main Protease Activity by the Zonulin Inhibitor Larazotide Acetate

et al. 2021

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“…Specifically, Govindaraj et al use BEDROC to assess the ability of their algorithm to detect protein pockets binding similar ligands [74]. Alberca et al use BEDROC to assess virtual screening of protein-ligand interactions [75]. Ajay Jain reports on limitations of BEDROC and other metrics that assess early enrichment from a virtual screening perspective, stating that they are biased to report elevated values based on the total number of positives and negatives [76].…”

Section: Boltzmann-enhanced Discrimination Of Receiver Operating Charmentioning

confidence: 99%

Evaluating Performance of Drug Repurposing Technologies

Schuler

Falls

Mangione

et al. 2020

Preprint

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Drug repurposing technologies are growing in number and maturing. However, comparison to each other and to reality is hindered due to lack of consensus with respect to performance evaluation. Such comparability is necessary to determine scientific merit and to ensure that only meaningful predictions from repurposing technologies carry through to further validation and eventual patient use. Here, we review and compare performance evaluation measures for these technologies using version 2 of our shotgun repurposing Computational Analysis of Novel Drug Opportunities (CANDO) platform to illustrate their benefits, drawbacks, and limitations. Understanding and using different performance evaluation metrics ensures robust cross platform comparability, enabling us to continuously strive towards optimal repurposing by decreasing time and cost of drug discovery and development.

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“…There are reports that they have implemented a computer-aided drug repurposing campaign to discover new inhibitors of falcipain-2. Four hits were acquired and tested against the enzyme, with two of them confirming inhibitory activity 34. The abandoned drug odanacatib displayed competitive inhibition, while the antibiotic methacycline also showed inhibitory effects through non-competitive inhibition 34.…”

Section: Reverse Docking To Find Drug Targets Of An Old Drugmentioning

confidence: 99%

“…Four hits were acquired and tested against the enzyme, with two of them confirming inhibitory activity 34. The abandoned drug odanacatib displayed competitive inhibition, while the antibiotic methacycline also showed inhibitory effects through non-competitive inhibition 34. Therefore, it is feasible to find the target of the old drug through reverse docking.…”

Section: Reverse Docking To Find Drug Targets Of An Old Drugmentioning

confidence: 99%

Artificial intelligence and big data facilitated targeted drug discovery

Liu

Luo

et al. 2019

Stroke Vasc Neurol

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Different kinds of biological databases publicly available nowadays provide us a goldmine of multidiscipline big data. The Cancer Genome Atlas is a cancer database including detailed information of many patients with cancer. DrugBank is a database including detailed information of approved, investigational and withdrawn drugs, as well as other nutraceutical and metabolite structures. PubChem is a chemical compound database including all commercially available compounds as well as other synthesisable compounds. Protein Data Bank is a crystal structure database including X-ray, cryo-EM and nuclear magnetic resonance protein three-dimensional structures as well as their ligands. On the other hand, artificial intelligence (AI) is playing an important role in the drug discovery progress. The integration of such big data and AI is making a great difference in the discovery of novel targeted drug. In this review, we focus on the currently available advanced methods for the discovery of highly effective lead compounds with great absorption, distribution, metabolism, excretion and toxicity properties.

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In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

Cited by 27 publications

References 113 publications

In silico Analysis Revealed Potential Anti-SARS-CoV-2 Main Protease Activity by the Zonulin Inhibitor Larazotide Acetate

In silico Analysis Revealed Potential Anti-SARS-CoV-2 Main Protease Activity by the Zonulin Inhibitor Larazotide Acetate

Evaluating Performance of Drug Repurposing Technologies

Artificial intelligence and big data facilitated targeted drug discovery

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