Finding alternatives to 5-fluorouracil: application of ensemble-based virtual screening for drug repositioning...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• 5-fluorouracil (5-FU) is a cornerstone chemotherapy for solid tumors, but resistance and toxicity limit its efficacy.
• Drug repurposing presents an avenue to identify novel anticancer agents with improved safety and effectiveness profiles.
• Human thymidylate synthase (hTS) is a validated target for anticancer drugs, including 5-FU.

Purpose of the Study:

• To identify FDA-approved drugs that can inhibit human thymidylate synthase (hTS).
• To evaluate the potential of repurposed drugs as alternatives or adjuncts to 5-FU chemotherapy.
• To investigate the binding interactions and energetics of drug-hTS complexes.

Main Methods:

• In silico screening of FDA-approved drugs against the human thymidylate synthase (hTS) active site.
• Molecular mechanics with the Poisson-Boltzmann and surface area (MM-PBSA) calculations to determine binding affinities.
• Analysis of non-covalent interactions, including van der Waals forces and the contribution of water molecules.

Main Results:

• Four FDA-approved drugs—Erismodegib, Irinotecan, Conivaptan, and Ergotamine—were prioritized for further validation.
• Ergotamine exhibited the lowest binding affinity to hTS (-66.702 ± 1.807 kJ/mol), indicating moderate inhibition.
• Significant van der Waals interactions contributed substantially to the binding energy of the hTS-Ergotamine complex (-190.889 ± 1.027 kJ/mol).

Conclusions:

• Repurposing FDA-approved drugs is a viable strategy to develop new cancer therapies targeting hTS.
• Ergotamine demonstrates potential as a moderate inhibitor of hTS, warranting further investigation for cancer treatment.
• Understanding the role of water and specific interactions is crucial for optimizing drug binding and efficacy.