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Exploring Novel Y140F/H Mutant Fungal CYP51 Inhibitors: A Molecular Docking and Dynamics Study on Thiophene Compounds
Abdulrahim A Alzain1, Alaa Edris1, Rua M Mukhtar1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan.
Background:
Invasive fungal infections (IFIs) pose a significant risk specifically to the health of immunocompromised individuals, leading to a substantial number of deaths annually. Therapeutic options for IFIs are limited compared to bacterial infections, with only three classes of antifungal medications currently in use. The widespread use of triazole antifungals for IFI prevention and treatment, along with long treatment durations, has led to the emergence of severe drug resistance, indicating the urgent need for intervention to address this critical issue. This study aims to identify novel inhibitors for the Y140F/H fungal CYP51 enzyme.
Methods:
Molecular docking and molecular dynamics were utilized to evaluate 161 thiophene compounds for their inhibitory potential against the mutant CYP51.
Findings:
The docking process involved two stages: docking on the wild type followed by docking on the mutant type, leading to the discovery of three compounds (referred to as compounds 1, 2, and 3) with better docking scores than the reference, indicating stronger binding affinity. Subsequent molecular dynamics simulations demonstrated that these three compounds displayed favorable stability and flexibility characteristics.
Conclusion:
Based on our findings, we suggest that compounds 1, 2, and 3 have the potential to act as inhibitors of the Y140F/H CYP51 enzyme.
Insights
This study identifies three novel thiophene compounds as potential inhibitors for the Y140F/H fungal CYP51 enzyme, addressing the urgent need for new antifungal drugs due to rising resistance. These compounds show promising binding affinity and stability for treating invasive fungal infections.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Mycology
Background:
- Invasive fungal infections (IFIs) are a major cause of mortality in immunocompromised patients.
- Limited antifungal drug classes and increasing triazole resistance necessitate novel therapeutic strategies.
- The Y140F/H mutant fungal CYP51 enzyme is a key target for antifungal drug development.
Purpose of the Study:
- To discover novel inhibitors targeting the Y140F/H fungal CYP51 enzyme.
- To evaluate the inhibitory potential of thiophene compounds against drug-resistant fungal strains.
- To identify lead compounds for the development of new antifungal agents.
Main Methods:
- Screening of 161 thiophene compounds using molecular docking against wild-type and mutant CYP51.
- In-depth analysis of binding affinity and interactions using molecular dynamics simulations.
- Evaluation of compound stability and flexibility.
Main Results:
- Three thiophene compounds (compounds 1, 2, and 3) exhibited superior docking scores compared to the reference drug.
- Molecular dynamics simulations confirmed the favorable stability and flexibility of these three compounds.
- The identified compounds demonstrate strong binding affinity to the Y140F/H CYP51 enzyme.
Conclusions:
- Compounds 1, 2, and 3 show significant potential as inhibitors of the Y140F/H fungal CYP51 enzyme.
- These compounds represent promising candidates for developing new treatments against invasive fungal infections.
- Further research is warranted to explore their therapeutic efficacy and safety profile.
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