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Insight into drug resistance mechanisms and discovery of potential inhibitors against wild-type and L1196M mutant ALK from FDA-approved drugs

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Abstract

Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified.

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Acknowledgments

We are grateful to Dr. Lei Wu (Sichuan University) for providing constructive suggestions. This work was supported in part by National Natural Science Foundation of China (Nos. 31300674, 81173093, 30970643, 81373311 and J1103518) and the Special Program for Youth Science and the Technology Innovative Research Group of Sichuan Province, China (No 2011JTD0026).

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    1. School of Life Sciences and Key laboratory of Bio-resources, Ministry of Education, Sichuan University, Chengdu, 610041, China

      Jianzong Li, Wei Liu, Hao Luo & Jinku Bao

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    1. Jianzong Li
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    2. Wei Liu
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    Correspondence to Jinku Bao.

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    Jianzong Li and Wei Liu contributed equally to this work.

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    Li, J., Liu, W., Luo, H. et al. Insight into drug resistance mechanisms and discovery of potential inhibitors against wild-type and L1196M mutant ALK from FDA-approved drugs. J Mol Model 22, 231 (2016). https://doi.org/10.1007/s00894-016-3099-5

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