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Can Duvelisib and Eganelisib work for both cancer and COVID-19? Molecular-level insights from MD simulations and
Saroj Kumar Panda1, Shaswata Karmakar1, Parth Sarthi Sen Gupta2
1Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Berhampur, Odisha 760010, India. mrana@iiserbpr.ac.in.
Abstract:
SARS-CoV-2 has caused severe illness and anxiety worldwide, evolving into more dreadful variants capable of evading the host's immunity. Cytokine storms, led by PI3Kγ, are common in cancer and SARS-CoV-2. Naturally, there is a yearning to see whether any drugs could alleviate cytokine storms for both. Upon investigation, we identified two anticancer drugs, Duvelisib and Eganelisib, that could also work against SARS-CoV-2. This report is the first to decipher their synergic therapeutic effectiveness against COVID-19 and cancer with molecular insights from atomistic simulations. In addition to PI3Kγ, these drugs exhibit specificity for the main protease among all SARS-CoV-2 targets, with significant negative binding free energies and small time-dependent conformational changes of the complexes. Complexation makes active sites and secondary structures highly mechanically stiff, with barely any deformation. Replica simulations estimated large pulling forces in enhanced sampling to dissociate the drugs from Mpro's active site. Furthermore, the radial distribution function (RDF) demonstrated that the therapeutic molecules were closest to the His41 and Cys145 catalytic dyad residues. Finally, analyses implied Duvelisib and Eganelisib as promising dual-purposed anti-COVID and anticancer drugs, potentially targeting Mpro and PI3Kγ to stop virus replication and cytokine storms concomitantly. We also distinguished hotspot residues imparting significant interactions.
Insights
Two anticancer drugs, Duvelisib and Eganelisib, show promise for treating both COVID-19 and cancer. These drugs target SARS-CoV-2
Area of Science:
- Oncology
- Virology
- Computational Chemistry
Background:
- SARS-CoV-2 variants pose global health risks, with cytokine storms contributing to severe illness.
- Cytokine storms, implicated in both cancer and COVID-19, are often mediated by PI3Kγ.
- Existing anticancer drugs may offer dual therapeutic potential against viral infections and cancer.
Purpose of the Study:
- To investigate the potential of anticancer drugs Duvelisib and Eganelisib as dual therapies for COVID-19 and cancer.
- To elucidate the molecular mechanisms underlying their synergistic therapeutic effectiveness.
- To identify specific SARS-CoV-2 targets and their interactions with these drug candidates.
Main Methods:
- Atomistic simulations were employed to analyze drug-target interactions.
- Binding free energies and conformational changes were calculated.
- Enhanced sampling techniques and replica simulations assessed drug-target binding stability.
- Radial distribution functions (RDF) were used to analyze molecular proximity.
Main Results:
- Duvelisib and Eganelisib demonstrated specificity for SARS-CoV-2 main protease (Mpro) in addition to PI3Kγ.
- Significant negative binding free energies indicated strong interactions with Mpro.
- Complexation resulted in mechanically stiff active sites with minimal deformation.
- Simulations revealed close proximity of drugs to the Mpro catalytic dyad (His41 and Cys145).
Conclusions:
- Duvelisib and Eganelisib are identified as promising dual-purpose drugs for anti-COVID-19 and anticancer applications.
- These drugs potentially target both Mpro to inhibit viral replication and PI3Kγ to mitigate cytokine storms.
- Key hotspot residues contributing to drug interactions were identified, offering insights for drug development.
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