Aims: Vismodegib is an effective antagonist of smoothened receptors for treatment of locally advanced or metastatic basal cell carcinoma. However, it often suffers from drug resistance due to mutations. Two common mutants, D473^6.55G and W535^7.55L, were found to cause serious drug resistance. Although the reduction of drug binding affinity (~40-fold) was thought to be the major reasons, the detailed structural, energetic and dynamic mechanisms at the molecular level are still unknown.

Main methods: Molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations were performed on three complex systems of wild-type (WT) and two mutants with vismodegib. Then, virtual screening was used to select three potential derivatives of vismodegib from the 7⁷ new derivatives designed by modifying the substitutions on the phenylpyridine ring of vismodegib.

Key findings: The MM-GBSA binding energy data of the two mutants showed a significant reduction in binding affinity. The energy decomposition identified that the key contributing residues were in the binding site. The D473^6.55G mutant affected the binding of the ligand by directly changing the conformations of the key residues in TM6, while the W535^7.55L mutant mainly depended on long range allosteric effect. More importantly, the methylsulfonyl benzamide moiety was identified to be the pharmacophore of the ligand, and two of the three derivatives from the virtual screening showed much higher MM-GBSA binding affinity to the two mutants than vismodegib did.

Significance: These results might help to understand resistance mechanisms and the two derivatives can be good candidates for future experiments.