Shengzheng Wang, Guoqiang Dong, Chunquan Sheng. Structural simplification:an efficient strategy in lead optimization[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 880-901

Structural simplification:an efficient strategy in lead optimization
Shengzheng Wanga,b, Guoqiang Donga, Chunquan Shenga
a Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China;
b Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.
Key words:    Structural simplification    Lead optimization    Drug discovery    Drug design    Reducing rings number    Reducing chiral centers    Structure-based simplification    Pharmacophore-based simplification   
Received: 2019-03-05     Revised: 2019-05-04
DOI: 10.1016/j.apsb.2019.05.004
Funds: This work was supported by the National Natural Science Foundation of China (Grant No. 81725020 to Chunquan Sheng and No. 21602252 to Shengzheng Wang), the Innovation Program of Shanghai Municipal Education Commission (Grant No. 2019-01-07-00-07-E00073 to Chunquan Sheng, China), and the Hong Kong Scholars Program (Grant No. XJ201713 to Shengzheng Wang, China).
Corresponding author: Guoqiang Dong, Chunquan Sheng;
Author description:
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Shengzheng Wang
Guoqiang Dong
Chunquan Sheng

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