A computational chemistry-driven hypothesis on the mode of action of hipposudoric acid and related analogs.

Aim: To elucidate the mode of action of the hipposudoric acid derivatives and identify hit compounds for synthesis. Materials & methods: Structural fragments of known bioactive fluorenes were introduced onto the hipposudoric acid scaffold to yield novel derivatives. The binding motifs of the novel compounds were compared to the pharmacophore of DHFR co-crystallized with methotrexate (MTX). Results: Several of the novel compounds showed binding affinities that exceeded the affinity of the docked endogenous ligand (dihydrofolic acid). Conclusion: This study indicates that compounds 3r 12 , 3r 9 , 1s 9 and 3r 10 are promising candidates for synthesis and pharmacological evaluation.