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

doi:10.1007/s11030-011-9317-2

	An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties
	Han, Chunyan 1,2; Zhang, Jinlan 1,2; Zheng, Mingyue3 ; Xiao, Yao 1,2; Li, Yan 1,2; Liu, Gang 1,2
刊名	MOLECULAR DIVERSITY
	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
DOI	10.1007/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.
资助项目	National 863 Program of China[2006AA020501] ; National Natural Science Foundation of China[90713045] ; Beijing Science Committee[Z0004105040231]
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
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000300364700005
内容类型	期刊论文
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.