Property distribution of drug-related chemical databases
Property distribution of drug-related chemical databases
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DOI：
10.1023/a:1008130001697
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发表时间：
2000-04-01
影响因子：
3.5
通讯作者：
Oprea, TI
中科院分区：
文献类型：
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作者：
Oprea, TI
化合物选择和优先排序的过程对于组合化学（CBC）和高通量筛选（HTS）都是至关重要的。化合物库必须筛选不需要的化学结构，以及不需要的化学性质。根据属性极值的实际分布，可以使用属性过滤器来消除属性极值。在以下化合物数据库中检查属性分布：MACCS-II药物数据报告（MDDR）、当前专利快速警报、综合药物化学、医师办公桌参考、新化学实体和可用化学目录（ACD）。ACDF和MDDRF子集是通过分别从ACD和MDDR数据库中删除反应性功能而创建的。通过只保留具有“药物样”评分的分子，进一步过滤ACDF子集[Ajay等人，J. Med. Chem]。， 41 (1998) 3314；Sadowski和Kubinyi， J. Med. Chem。， 41(1998) 3325]低于0.8。考察了其分子量（MW）、辛醇/水分配系数（CLOGP）、可旋转键数（RTB）和刚性键数（RGB）、环数（RNG）、氢键供体数（HDO）和受体数（HAC）。其中，MW和CLOGP遵循高斯分布，而所有其他描述符具有不对称（截断的高斯）分布。ACDF和MDDRF中的5个化合物中有4个通过了“5规则”测试，这是Lipinski等人提出的一种估计口服吸收的概率方案。启示录，23(1997)[3]。由于HDO、HAC、MW和CLOGP的属性分布（用于“5法则”检验）在这些数据集之间没有显著差异，因此“5法则”不能区分“药物”和“非药物”。因此，执行帕累托分析来检查所有化合物集合中的倾斜分布。70%的“类药”化合物在以下范围内被发现：0小于或等于HDO小于或等于2,2小于或等于HAC小于或等于9,2小于或等于RTB小于或等于8,1小于或等于RNG小于等于4。在MDDR中，0小于等于HDO小于等于2的上市药物数量是3小于等于HDO小于等于5的上市药物数量的4.8倍。偏态分布可以用来关注“类药物空间”：62.68%的ACDF（“非类药物”）化合物的0小于等于RNG小于等于2，RGB小于等于17，而28.88%的ACDF化合物的3小于等于RNG小于等于13,18小于等于RGB小于等于56。相比之下，61.22%的MDDRF化合物RNG大于等于3，RGB大于等于18，只有24.73%的MDDRF化合物小于等于RNG小于等于2环，RGB小于等于17。识别“类药物”结构的可能性随着分子复杂性的增加而增加。
The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters, in accordance with their actual distribution. Property distribution was examined in the following compound databases: MACCS-II Drug Data Report (MDDR), Current Patents Fast-alert, Comprehensive Medicinal Chemistry, Physician Desk Reference, New Chemical Entities, and the Available Chemical Directory (ACD). The ACDF and MDDRF subsets were created by removing reactive functionalities from the ACD and MDDR databases, respectively. The ACDF subset was further filtered by keeping only molecules with a 'drug-like' score [Ajay et al., J. Med. Chem., 41 (1998) 3314; Sadowski and Kubinyi, J. Med. Chem., 41 (1998) 3325] below 0.8. The following properties were examined: molecular weight (MW), the calculated octanol/water partition coefficient (CLOGP), the number of rotatable (RTB) and rigid bonds (RGB), the number of rings (RNG), and the number of hydrogen bond donors (HDO) and acceptors (HAC). Of these, MW and CLOGP follow a Gaussian distribution, whereas all other descriptors have an asymmetric (truncated Gaussian) distribution. Four out of five compounds in ACDF and MDDRF pass the 'rule of 5' test, a probability scheme that estimates oral absorption proposed by Lipinski et al. [Adv. Drug Deliv. Rev., 23 (1997) 3]. Because property distributions of HDO, HAC, MW and CLOGP (used in the 'rule of 5' test) do not differ significantly between these datasets, the 'rule of 5' does not distinguish 'drugs' from 'nondrugs'. Therefore, Pareto analyses were performed to examine skewed distributions in all compound collections. Seventy percent of the `drug-like' compounds were found between the following limits: 0 less than or equal to HDO less than or equal to 2, 2 less than or equal to HAC less than or equal to 9, 2 less than or equal to RTB less than or equal to 8, and 1 less than or equal to RNG less than or equal to 4, respectively. The number of launched drugs in MDDR having 0 less than or equal to HDO less than or equal to 2 is 4.8 times higher than the number of drugs having 3 less than or equal to HDO less than or equal to 5. Skewed distributions can be exploited to focus on the 'drug-like space': 62.68% of ACDF ('nondrug-like') compounds have 0 less than or equal to RNG less than or equal to 2, and RGB less than or equal to 17, while 28.88% of ACDF compounds have 3 less than or equal to RNG less than or equal to 13, and 18 less than or equal to RGB less than or equal to 56. By contrast, 61.22% of MDDRF compounds have RNG greater than or equal to 3, and RGB greater than or equal to 18, and only 24.73% of MDDRF compounds have 0 less than or equal to RNG less than or equal to 2 rings, and RGB less than or equal to 17. The probability of identifying 'drug-like' structures increases with molecular complexity.