Proposal of novel potent inhibitors against androgen receptor based on ab initio molecular orbital calculations.

Shunya Nakamura, Ryosuke Saito, Shohei Yamamoto, Ittetsu Kobayashi, Ryosuke Takeda, Rie Suzuki, Kentaro Kawai, Midori Takimoto-Kamimura, Noriyuki Kurita

Journal of molecular graphics & modelling 2021 Jun

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The androgen receptor (AR), a family of nuclear receptor proteins, stimulates the transcription of androgen-responsive genes. As its abnormal activation can cause the progression of prostate cancer, numerous types of ligands for AR have been developed as promising antagonists for the treatment of prostate cancer. We previously investigated the specific interactions between AR and nine types of existing non-steroidal ligands, using molecular simulations based on molecular mechanics and ab initio fragment molecular orbital methods. The results were confirmed to be comparable to the binding affinities of these ligands observed in experiments. We here propose novel ligands as potent inhibitors against AR and investigate their binding properties to AR, using the same molecular simulations. The results indicate that the most promising ligand binds stronger to AR than the existing non-steroidal ligands, and that our proposed ligand binds strongly to a mutant-type AR, which has drug resistance to the existing non-steroidal ligands. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Shunya Nakamura, Ryosuke Saito, Shohei Yamamoto, Ittetsu Kobayashi, Ryosuke Takeda, Rie Suzuki, Kentaro Kawai, Midori Takimoto-Kamimura, Noriyuki Kurita. Proposal of novel potent inhibitors against androgen receptor based on ab initio molecular orbital calculations. Journal of molecular graphics & modelling. 2021 Jun;105:107873