caa a22 4500 445878800 CHVBK 20180317145535.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11030-011-9317-2 doi (NATIONALLICENCE)springer-10.1007/s11030-011-9317-2 An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties [Elektronische Daten] [Chunyan Han, Jinlan Zhang, Mingyue Zheng, Yao Xiao, Yan Li, Gang Liu] 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. Springer Science+Business Media B.V., 2011 Physicochemical properties nationallicence Pharmacokinetic properties nationallicence Privileged structure nationallicence Drug-likeness nationallicence ADME nationallicence ACD-p : Available chemicals directory-privileged structures nationallicence ADME/T : Absorption, distribution, metabolism, elimination and toxicity nationallicence ALogP : Calculated Octanol-Water partition coefficient nationallicence CMC-r : Comprehensive medicinal chemistry-remain nationallicence CMC-p : Comprehensive medicinal chemistry-privileged structures nationallicence DMSO : Dimethyl sulfoxide nationallicence DLR : Drug-like range nationallicence ESI : Electrospray ionization nationallicence FITC : Fluorescein isothiocyanate nationallicence FPSA : Fraction of polar surface area in total surface area nationallicence Hacc : Number of hydrogen-bond acceptors nationallicence Hdon : Number of hydrogen-bond donors nationallicence HPLC : High-performance liquid chromatography nationallicence LC/MS : Liquid chromatography mass spectrometry nationallicence LogD : Calculated Octanol-Water distribution coefficient nationallicence MDDR-p : Medicinal drug data report-privileged structures nationallicence MR : Molar refractivity nationallicence MW : Molecular weight nationallicence Nc : Number of chain assembles nationallicence Nr : Number of rings nationallicence P app : Apparent permeability coefficient nationallicence PCP : Physicochemical property nationallicence PK : Pharmacokinetic nationallicence PSA : Polar surface area nationallicence RotB : Number of rotatable bonds nationallicence RP : Recursive partition nationallicence Rt : Retention time nationallicence SA : Number of stereo atoms nationallicence Tris : N-tris(hydroxymethyl)aminomethane nationallicence Han Chunyan Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut Zhang Jinlan Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut Zheng Mingyue Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang High-Tech Park, 201203, Shanghai, China aut Xiao Yao Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut Li Yan Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut Liu Gang Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut Molecular Diversity Springer Netherlands 15/4(2011-11-01), 857-876 1381-1991 15:4<857 2011 15 11030 https://doi.org/10.1007/s11030-011-9317-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11030-011-9317-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Han Chunyan Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut NATIONALLICENCE 700 1- Zhang Jinlan Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut NATIONALLICENCE 700 1- Zheng Mingyue Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang High-Tech Park, 201203, Shanghai, China aut NATIONALLICENCE 700 1- Xiao Yao Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut NATIONALLICENCE 700 1- Li Yan Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut NATIONALLICENCE 700 1- Liu Gang Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China aut NATIONALLICENCE 773 0- Molecular Diversity Springer Netherlands 15/4(2011-11-01), 857-876 1381-1991 15:4<857 2011 15 11030 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer