Finding alternatives to 5-fluorouracil: application of ensemble-based virtual screening for drug repositioning against human thymidylate synthase

Abstract

5-fluorouracil and analogs are used in the treatment of many solid tumours. However, there are many cases of resistance and high toxicity associated with 5-fluorouracil chemotherapy. Repurposing FDA drugs against human thymidylate synthase revealed a number of FDA drugs that have a potential to be further developed for the treatment of various cancers for which 5-fluorouracil and analogs have been used for chemotherapy. Four FDA drugs prioritized for further validation included Erismodegib, Irinotecan, Conivaptan and Ergotamine. The role of water in mediating drug interactions and its contribution to the total binding energy was also shown. MM-PBSA calculations revealed that the binding affinity was the lowest for the hTS-Ergotamine complex (–66.702 ± 1.807 kJ/mol) suggesting moderate inhibition despite a large energetic contribution from van der Waal interactions (–190.889 ± 1.027 kJ/mol). Communicated by Ramaswamy H. Sarma