通过探索结合口袋动力学来扩展 SIRT2 抑制剂的可及化学空间,Journal of Chemical Information and Modeling

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通过探索结合口袋动力学来扩展 SIRT2 抑制剂的可及化学空间
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-04-25 , DOI: 10.1021/acs.jcim.2c00241
Nemanja Djokovic ₁ , Dusan Ruzic ₁ , Minna Rahnasto-Rilla ₂ , Tatjana Srdic-Rajic ₃ , Maija Lahtela-Kakkonen ₂ , Katarina Nikolic ₁

Affiliation

结合口袋动力学的考虑是合理设计活页夹的关键方面之一。识别替代构象状态或神秘的子口袋可能导致发现全新的配体组。然而，口袋动力学的实验表征，除了昂贵之外，可能无法阐明与药物发现项目相关的所有构象状态。在这项研究中，我们提出了用于计算模拟 sirtuin 2 (SIRT2) 结合口袋动力学的协议，并将其集成到基于结构的虚拟筛选 (SBVS) 管道中。最初，使用 SIRT2 抑制剂的优化力场参数进行 SIRT2：抑制剂复合物的无偏分子动力学模拟。时滞独立分量分析 (tICA) 用于设计与口袋相关的集体变量 (CV)，以增强对 SIRT2 口袋动力学的采样。tICA 特征向量空间中的元动力学模拟揭示了 SIRT2 结合口袋的替代构象状态和神秘子口袋的存在。在回顾性 SBVS 验证中，新发现的 SIRT2 构象状态优于实验解决状态。在进行前瞻性 SBVS 后，选择了来自 SIRT2 抑制剂化学空间中代表性不足部分的化合物在回顾性 SBVS 验证中，新发现的 SIRT2 构象状态优于实验解决状态。在进行前瞻性 SBVS 后，选择了来自 SIRT2 抑制剂化学空间中代表性不足部分的化合物在回顾性 SBVS 验证中，新发现的 SIRT2 构象状态优于实验解决状态。在进行前瞻性 SBVS 后，选择了来自 SIRT2 抑制剂化学空间中代表性不足部分的化合物体外评价。两种化合物 NDJ18 和 NDJ85 被鉴定为有效和选择性的 SIRT2 抑制剂，这验证了计算机方案并为其应用的推广和拓宽开辟了可能性。在三阴性乳腺癌细胞系中检测了最有效的化合物 NDJ18 的抗癌作用。结果表明，NDJ18 代表了一种有前途的结构，适合进一步评估。

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Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics

Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.

更新日期：2022-04-25

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