关键词： 11β-HSD, 11β-hydroxysteroid dehydrogenase 3D, three-dimensional ADMET, absorption, distribution, metabolism, excretion and toxicity AM2, adrenomedullin-2 receptor BIOS, biology-oriented synthesis CCK, cholecystokinin receptor CGRP, calcitonin gene-related peptide Drug design Drug discovery GlyT1, glycine transport 1 HBV, hepatitis B virus HDAC, histone deacetylase HLM, human liver microsome JAKs, Janus tyrosine kinases LE, ligand efficiency Lead optimization LeuRS, leucyl-tRNA synthetase MCRs, multicomponent reactions MDR-TB, multidrug-resistant tuberculosis MW, molecular weight NP, natural product NPM, nucleophosmin PD, pharmacodynamic PK, pharmacokinetic PKC, protein kinase C Pharmacophore-based simplification Reducing chiral centers Reducing rings number SAHA, vorinostat SAR, structure‒activity relationship SCONP, structural classification of natural product Structural simplification Structure-based simplification TSA, trichostatin A TbLeuRS, T. brucei LeuRS ThrRS, threonyl-tRNA synthetase VANGL1, van-Gogh-like receptor protein 1 aa-AMP, aminoacyl-AMP aa-AMS, aminoacylsulfa-moyladenosine aaRSs, aminoacyl-tRNA synthetases hA3 AR, human A3 adenosine receptor mTORC1, mammalian target of rapamycin complex 1

来  源：   DOI：10.1016/j.apsb.2019.05.004   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
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.
摘要：
设计用于铅优化的大疏水分子的趋势通常与药物发现和开发中的不良药物相似度和高磨耗率有关。结构简化是通过避免“分子肥胖”来提高药物设计效率和成功率的有力策略。通过截断不必要的基团对大型或复杂的先导化合物进行结构简化，不仅可以提高其合成可及性，而且可以改善其药代动力学特征，减少副作用等。本文将总结结构简化在引线优化中的应用。大量的案例研究，特别是那些涉及成功的例子，导致上市药物或类似药物的候选药物，将进行介绍和分析，以说明结构简化的设计策略和准则。
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