An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties |
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Authors: | Chunyan Han Jinlan Zhang Mingyue Zheng Yao Xiao Yan Li Gang Liu |
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Institution: | (1) Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China;(2) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang High-Tech Park, Shanghai, 201203, China; |
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Abstract: | 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. |
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