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High-throughput and intelligent design of potential GRK2 inhibitor candidates using deep learning and mathematical programming methods 认领 引用
1
作者 Yujing Zhao Qilei Liu +3 位作者 Jian Du Qingwei Meng Liang Sun Lei Zhang 《Chinese Journal of Chemical Engineering》 SCIE EI CAS CSCD 2025年第8期11-22,共12页
G protein coupled receptor kinase 2 (GRK2) is a kinase that regulates cardiac signaling activity. Inhibiting GRK2 is a promising mechanism for the treatment of heart failure (HF). Further development and optimization ... G protein coupled receptor kinase 2 (GRK2) is a kinase that regulates cardiac signaling activity. Inhibiting GRK2 is a promising mechanism for the treatment of heart failure (HF). Further development and optimization of inhibitors targeting GRK2 are highly meaningful. Therefore, in order to design GRK2 inhibitors with better performance, the most active molecule was selected as a reference compound from a data set containing 4-pyridylhydrazone derivatives and triazole derivatives, and its scaffold was extracted as the initial scaffold. Then, a powerful optimization-based framework for de novo drug design, guided by binding affinity, was used to generate a virtual molecular library targeting GRK2. The binding affinity of each virtual compound in this dataset was predicted by our developed deep learning model, and the designed potential compound with high binding affinity was selected for molecular docking and molecular dynamics simulation. It was found that the designed potential molecule binds to the ATP site of GRK2, which consists of key amino acids including Arg199, Gly200, Phe202, Val205, Lys220, Met274 and Asp335. The scaffold of the molecule is stabilized mainly by H-bonding and hydrophobic contacts. Concurrently, the reference compound in the dataset was also simulated by docking. It was found that this molecule also binds to the ATP site of GRK2. In addition, its scaffold is stabilized mainly by H-bonding and π-cation stacking interactions with Lys220, as well as hydrophobic contacts. The above results show that the designed potential molecule has similar binding modes to the reference compound, supporting the effectiveness of our framework for activity-focused molecular design. Finally, we summarized the interaction characteristics of general GRK2 inhibitors and gained insight into their molecule-target binding mechanisms, thereby facilitating the expansion of lead to hit compound. 展开更多
关键词 Mathematical modeling Optimal design Product design GRK2 Mathematical programmingmethod Binding affinity
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大鹏湾环境容量研究Ⅱ:环境容量规划 认领 引用 被引量：10
2
作者 夏华永 李绪录 韩康 《中国环境科学》 CAS CSCD 北大核心 2011年第12期2039-2045,共7页
采用基于响应场的线性规划方法,考虑非点源与湾外污染物输入形成的本底值,结合深圳沿岸排污口的分布计算了大鹏湾的环境容量,并给出了总量分配方案.结果表明,大鹏湾物理自净能力差,但水体容量大,具有较大的稀释容量,加上污染物的生化降... 采用基于响应场的线性规划方法,考虑非点源与湾外污染物输入形成的本底值,结合深圳沿岸排污口的分布计算了大鹏湾的环境容量,并给出了总量分配方案.结果表明,大鹏湾物理自净能力差,但水体容量大,具有较大的稀释容量,加上污染物的生化降解,大鹏湾具有较大的环境容量.BOD5、总氮、总磷的最大允许排放总量分别为79.0,11.418,0.86t/d,BOD5、总氮、总磷的剩余环境容量分别为61.34,9.318,0.43t/d. 展开更多
关键词 大鹏湾 环境容量 响应场 线性规划
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