胞液型磷脂酶A2能引发关节炎，针对胞液型磷脂酶A2的抑制剂有可能成为治疗关节炎的特效药，因此引起了广泛的关注.文章对于吡咯烷类胞液型磷脂酶A2抑制剂进行了三维定量构效关系研究，利用比较分子力场分析构建了该类分子的定量构效关系，得到三维等值线图，为胞液型磷脂酶A2抑制剂的进一步改造提供了有益的启示。

The SARS coronavirus 3C-like proteinase is considered as a potential drug design target for the treatment of severe acute respiratory syndrome (SARS). Owing to the lack of available drugs for the treatment of SARS, the discovery of inhibitors for SARS coronavirus 3C-like proteinase that can potentially be optimized as drugs appears to be highly desirable. We have built a “flexible” three-dimensional model for SARS 3C-like proteinase by homology modeling and multicanonical molecular dynamics method and used the model for virtual screening of chemical databases. After Dock procedures, strategies including pharmocophore model, consensus scoring, and “drug-like” filters were applied in order to accelerate the process and improve the success rate of virtual docking screening hit lists. Forty compounds were purchased and tested by HPLC and colorimetric assay against SARS 3C-like proteinase. Three of them including calmidazolium, a wellknown antagonist of calmodulin, were found to inhibit the enzyme with an apparent Ki from 61 to 178 μM. These active compounds and their binding modes provide useful information for understanding the binding sites and for further selective drug design against SARS and other coronavirus.

采用“结合强度指纹图谱分析”方法、通过对多重分子对接得到的作用强度数据进行聚类矩阵分析对蛋白质进行功能分类。 着重研究了磷脂酶A2家族基于抑制剂作用强度的功能分类、 并且与基于序列的聚类结果进行比较、 成功地解决了序列比对方法不能处理的远源蛋白（cPLA2）的分类问题。

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.

We have developed a new docking method, Pose-Sensitive Inclined (PSI)-DOCK, for flexible ligand docking. An improved SCORE function has been developed and used in PSI-DOCK for binding free energy evaluation. The improved SCORE function was able to reproduce the absolute binding free energies of a training set of 200 protein-ligand complexes with a correlation coefficient of 0.788 and a standard error of 8.13 kJ/mol. For ligand binding pose exploration, a unique searching strategy was designed in PSI-DOCK. In the first step, a tabu-enhanced genetic algorithm with a rapid shape complementary scoring function is used to roughly explore and store potential binding poses of the ligand. Then, these predicted binding poses are optimized and compete against each other by using a genetic algorithm with the accurate SCORE function to determine the binding pose with the lowest docking energy. The PSI-DOCK 1.0 program is highly efficient in identifying the experimental binding pose. For a test dataset of 194 complexes, PSI-DOCK 1.0 achieved a 67% success rate (RMSD <2.0Å) for only one run and a 74% success rate for 10 runs. PSI-DOCK can also predict the docking binding free energy with high accuracy. For a test set of 64 complexes, the correlation between the experimentally observed binding free energies and the docking binding free energies for 64 complexes is r =0.777 with a standard deviation of 7.96 kJ/mol. Moreover, compared with other docking methods, PSIDOCK 1.0 is extremely easy to use and requires minimum docking preparations. There is no requirement for the users to add hydrogen atoms to proteins because all protein hydrogen atoms and the flexibility of the terminal protein atoms are intrinsically taken into account in PSI-DOCK. There is also no requirement for the users to calculate partial atomic charges because PSI-DOCK does not calculate an electrostatic energy term. These features are not only convenient for the users but also help to avoid the influence of different preparation methods. Proteins 2006; 62:934–946.

Virtual screen by molecular docking has been successfully applied in lead discovery. However, it suffers from huge computational time, difficulties in final compounds selection, and correct binding pose prediction. We have developed a combined comprehensive “virtual screening” strategy and successfully applied to identify antagonist of HLA-DR4 from a pool of 4,000,000 chemical compounds based on the complex crystal structure of human HLA-DR4 bound with influenza ha antigen peptide. Five compounds were selected and tested in a cell based assay and two non-peptide compounds exhibited 17μM and 31μM inhibitory effects in the cell competitive test with the peptide collagen II against HLA-DR4, which function equivalently or better than those peptide antagonists. These compounds are among the first examples of potent, non-peptide antagonists for the HLA-DR4, which should be useful for further development of non-peptide anti-rheumatoid arthritis drugs.

The ubiquitin-proteasome pathway plays a crucial role in the regulation of many physiological processes and in the development of a number of major human diseases, such as cancer, Alzheimer, Parkinson, diabetes etc. As a new target, the study on the proteasome inhibitors has received much attention recently. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using comparative molecule field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) techniques were applied to analyze the binding affinity of a set of tripeptide aldehyde inhibitors of 20S proteasome. The optimal CoMFA and CoMSIA models obtained for the training set were all statistically significant with cross-validated coefficients (q2) of 0.615, 0.591 and conventional coefficients (r2) of 0.901, 0.894, respectively. These models were validated by a test set of 8 molecules that were not included in the training set. The predicted correlation coefficients (r2) of CoMFA and CoMSIA are 0.944 and 0.861, respectively. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of β5 subunit of 20S proteasome, which suggests that the 3D-QSAR models built in this paper can be used to guide the development of novel inhibitors of 20S proteasome

系统生物学的迅速发展和研究成果揭示了越来越多的蛋白与蛋白、蛋白与小分子化合物之间的相互作用关系、功能以及亚细胞分布信息；进而推动后基因组时代的药物设计从考虑单一的受体结构转向综合考虑配体分子与多种蛋白的作用、以便在尽可能早的设计阶段就能找出分子在人体内可能作用的受体类型及其可能的药效、或者预测其可能的副作用并加以避免。在实验室设计开发的人类疾病相关蛋白质结构数据库（Human Diseases Related Protein Database、 HDRPD）的基础上、我们提出了基于药效团匹配和分子对接的化合物评价策略：以配体分子为提问结构对人类疾病相关蛋白质结构数据库进行反向筛选、根据筛选结果可以得到提问分子在人体内可能的作用受体、并以此为依据进行分子结构改造、以加强配体分子的结合专一性；或者发现提问分子的新型结合受体开发其潜在应用功能。本文选取环氧合酶2 的专一性抑制剂Rofecoxib 和叶酸分子、磷脂酶A2 的抑制剂、按照药效团匹配和分子对接两种方法进行反向筛选评价、结果很好的与实验事实吻合、并且较好的解释了药物分子的某些毒副作用的机理、为未知化合物的功能预测和“老药新用”提供了一种新方法、新思路。

The “human diseases related proteins and bio-active molecule database” is a web-based knowledge base, which provides information for protein sequences, structures, annotations, drug interactions and diseases for over 2200 drug targets. The provided reverse pharmacophore search and invert-docking tools can be used to search the database for potential protein targets or chemical compounds. Integration of such data provides decent interface to data mining of disease related molecular interactions. The database can be accessed at http://www.hdrp-bd.org.