Effect of mutations on drug resistance of smoothened receptor toward inhibitors probed by molecular modeling

The smoothened receptor (SMO) plays a critical role in embryonic development. Vismodegib was approved by the FDA to treat metastatic basal-cell carcinoma. However, The D473H mutation can cause obvious drug resistance toward Vismodegib. In this work, the drug-resistance mechanisms of three molecules were explored by theoretical calculations. The results indicate that the D473H mutation can disrupt the hydrogen-bonding network in the binding pocket, which can weaken the binding of Vismodegib. Whereas, for LY2940680 and L4 there are new hydrogen bond networks formed, which can stabilize their binding. This work provides a theoretical contribution to design more promising SMO inhibitors.