Pei Jianfeng, Chen Hao, Liu Zhenming, Han Xiaofeng, Wang Qi, Shen Bin, Zhou Jiaju, Lai Luhua
State Key Laboratory for Structural Chemistry of Stable and Unstable Species, College of Chemistry and Molecular Engineering and Center for Theoretical Biology, Peking University, Beijing 100871, China.
J Chem Inf Model. 2005 Nov-Dec;45(6):1920-33. doi: 10.1021/ci050203c.
To address the problems associated with molecular conformations and alignments in the 3D-QSAR studies, we have developed the Flexible Ligand - Atomic Receptor Model (FLARM) 2.0 method. The FLARM 2.0 method has three unique features as compared to other pseudoreceptor model methods: (1) the training ligands are flexibly optimized inside the receptors to achieve minimal docking energies; (2) the receptor atoms are spatially moveable in the process of genetic evolving in order to avoid improper initial receptor shapes; and (3) void receptor sites are specially favored in order to obtain open receptor models that allow large gaps. Advantages of an open model include less noise information, a smaller risk of overfitting, and ease of locating the key interaction sites. The latter two features, inherited from the previous FLARM 1.0 method, can improve the predictive ability of the 3D-QSAR models, while the first feature is newly implemented to relieve the uncertainty caused by improper conformation and alignment. Three FLARM 2.0 case studies were performed, and the results show that FLARM 2.0 models are highly predictive and robust. FLARM 2.0 pseudoreceptor models can correspond well with the pharmacophore models and/or the binding sites of the real protein receptors.
为了解决三维定量构效关系（3D-QSAR）研究中与分子构象和排列相关的问题，我们开发了灵活配体-原子受体模型（FLARM）2.0方法。与其他虚拟受体模型方法相比，FLARM 2.0方法具有三个独特的特点：（1）训练配体在受体内部进行灵活优化，以实现最小对接能量；（2）受体原子在遗传进化过程中可在空间上移动，以避免初始受体形状不当；（3）特别青睐空的受体位点，以获得允许有大间隙的开放受体模型。开放模型的优点包括噪声信息少、过拟合风险小以及易于定位关键相互作用位点。后两个特点继承自先前的FLARM 1.0方法，可以提高3D-QSAR模型的预测能力，而第一个特点是新实施的，以缓解由构象和排列不当引起的不确定性。进行了三个FLARM 2.0案例研究，结果表明FLARM 2.0模型具有高度的预测性和稳健性。FLARM 2.0虚拟受体模型可以与药效团模型和/或真实蛋白质受体的结合位点很好地对应。
