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Targeting COVID-19 and varicocele by blocking inflammasome: Ligand-based virtual screening
Haitham Al-Madhagi1, Muhammed Tilahun Muhammed2
1Biochemical Technology Program, Thamar University, Dhamar, Yemen.
Abstract:
COVID-19 is a new generation of outbreaks that invade not only local emerging region, continental but also the whole globe. Varicocele on the other hand, is a testicular vascular disease that underlies 40 % of male infertility cases. Fortunately, the two diseases can be blocked through targeting one common target, NLRP3 inflammasome. Upon searching for similar drugs that gained FDA-approval in ChEMBL library along with examining their potential blockade of the receptor through docking using CB-DOCK-2, three potential approved drugs can be repurposed, ChEMBL 4297185, ChEMBL 1201749, ChEMBL 1200545 which had binding energy of -9.8 and -9.7 kcal/mol (stronger than the reference inhibitor, -9.3 kcal/mol). Also, ADME profile of the top 3 drugs showed better attributes. Also, the simulated proteins exhibited stable pattern with strong free binding energies. Among the potential inhibitor drugs ChEMBL 4297185 was found to remain inside the binding site of the protein during the 200 ns simulation time. Hence, it is anticipated to have the highest binding and thus inhibition potential against the protein. The suggested drugs, especially ChEMBL 4297185, are potentially repurposable toward treating COVID-19 and varicocele which deserve further experimental validation.
Insights
Repurposing FDA-approved drugs to target the NLRP3 inflammasome offers a novel strategy for treating both COVID-19 and varicocele. ChEMBL 4297185 demonstrated significant binding affinity and stability, suggesting high therapeutic potential.
Area of Science:
- Computational drug discovery
- Molecular pharmacology
- Infectious disease research
Background:
- COVID-19 is a global pandemic affecting respiratory health.
- Varicocele is a leading cause of male infertility.
- NLRP3 inflammasome is a common therapeutic target for both conditions.
Purpose of the Study:
- To identify FDA-approved drugs for repurposing against COVID-19 and varicocele.
- To evaluate the binding potential of candidate drugs targeting the NLRP3 inflammasome.
- To assess the pharmacokinetic properties and stability of potential drug candidates.
Main Methods:
- Database screening (ChEMBL) for FDA-approved drugs.
- Molecular docking simulations (CB-DOCK2) to predict binding affinity.
- ADME profiling and molecular dynamics simulations for stability assessment.
Main Results:
- Three FDA-approved drugs (ChEMBL 4297185, 1201749, 1200545) showed strong binding energies (-9.8 to -9.7 kcal/mol) against NLRP3 inflammasome.
- ChEMBL 4297185 exhibited superior binding affinity and remained stable within the protein's binding site during 200 ns simulations.
- The identified drugs demonstrated favorable ADME profiles.
Conclusions:
- ChEMBL 4297185 is a promising drug candidate for repurposing in COVID-19 and varicocele treatment.
- Targeting the NLRP3 inflammasome with repurposed drugs is a viable therapeutic strategy.
- Further experimental validation is warranted to confirm the efficacy of these repurposed drugs.
