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An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties

文献类型：期刊论文

作者Han, Chunyan1,2; Zhang, Jinlan1,2; Zheng, Mingyue3; Xiao, Yao1,2; Li, Yan1,2; Liu, Gang1,2
刊名MOLECULAR DIVERSITY
出版日期2011-11
卷号15期号:4页码:857-876
关键词Physicochemical properties Pharmacokinetic properties Privileged structure Drug-likeness ADME
ISSN号1381-1991
DOI10.1007/s11030-011-9317-2
文献子类Article
英文摘要The concept of drug-likeness has been widely applied in combinatorial chemistry as an approach to reduce attrition in drug discovery and development. Meanwhile, bicyclic privileged structures with versatile binding properties have emerged as ideal source of core scaffolds for the design and synthesis of combinatorial libraries. For the purpose of better assisting the design of bicyclic privileged structure-based combinatorial libraries, we conducted an integrated drug-likeness study on compounds of these scaffolds. Distributions of physicochemical properties (PCPs) were analyzed and in silico prediction models were built. Our results showed that there exist much difference between the drug-like ranges(DLRs) of bicyclic privileged structures and that of others, which have significant impact on compound selection. The DLRs for bicyclic privileged structures were defined as 260 <= MW <= 524; 0.9 <= ALogP <= 5.4; 2 <= Hacc <= 8; Hdon <= 3; 21.0 <= PSA <= 128.6; 6.3 <= FPSA <= 34.2; 1 <= RotB <= 10; 2 <= Nr <= 5; 1 <= Nc <= 7; SA <= 4. Two accurate and easy to understand in silico prediction models, Caco-2 permeability model and metabolic stability classification model, had been built to guide drug candidate optimization. In these models, hydrogen-bond donor and rotatable bond showed major impact on the permeability of compounds, while lipophilicity, flexibility, degree of branching and the existence of some functional groups determined the fate of a drug in metabolic process. Suggestions on structural modification toward higher permeability and metabolic stability were given according to the in silico models.
WOS关键词CACO-2 CELL-PERMEABILITY ; PHASE PARALLEL SYNTHESIS ; MOLECULAR-SURFACE PROPERTIES ; INTESTINAL-ABSORPTION ; ORAL BIOAVAILABILITY ; SECRETORY TRANSPORT ; SELECTION CRITERIA ; PREDICTION ; DISCOVERY ; MODEL
资助项目National 863 Program of China[2006AA020501] ; National Natural Science Foundation of China[90713045] ; Beijing Science Committee[Z0004105040231]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000300364700005
出版者SPRINGER
源URL[http://119.78.100.183/handle/2S10ELR8/278340]  
专题药物化学研究室
通讯作者Liu, Gang
作者单位1.Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China;
2.Peking Union Med Coll, Beijing 100050, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Han, Chunyan,Zhang, Jinlan,Zheng, Mingyue,et al. An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties[J]. MOLECULAR DIVERSITY,2011,15(4):857-876.
APA Han, Chunyan,Zhang, Jinlan,Zheng, Mingyue,Xiao, Yao,Li, Yan,&Liu, Gang.(2011).An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties.MOLECULAR DIVERSITY,15(4),857-876.
MLA Han, Chunyan,et al."An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties".MOLECULAR DIVERSITY 15.4(2011):857-876.

入库方式： OAI收割

来源：上海药物研究所

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