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.

平滑受体（SMO）在胚胎发育中起关键作用。Vismodegib被FDA批准用于治疗转移性基底细胞癌。但是，D473H突变可导致对Vismodegib的明显耐药性。在这项工作中，通过理论计算探索了三种分子的耐药机制。结果表明，D473H突变可破坏结合口袋中的氢键网络，从而削弱Vismodegib的结合。而对于LY2940680和L4，形成了新的氢键网络，可以稳定它们的结合。这项工作为设计更有希望的SMO抑制剂提供了理论上的帮助。