1. Structural simplification: an efficient strategy in lead optimization
- Author
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Chunquan Sheng, Shengzheng Wang, and Guoqiang Dong
- Subjects
ThrRS, threonyl-tRNA synthetase ,Computer science ,GlyT1, glycine transport 1 ,HDAC, histone deacetylase ,Review ,MW, molecular weight ,CGRP, calcitonin gene-related peptide ,0302 clinical medicine ,LeuRS, leucyl-tRNA synthetase ,TSA, trichostatin A ,General Pharmacology, Toxicology and Pharmaceutics ,media_common ,0303 health sciences ,aa-AMP, aminoacyl-AMP ,Drug discovery ,mTORC1, mammalian target of rapamycin complex 1 ,Hbv hepatitis b virus ,11β-HSD, 11β-hydroxysteroid dehydrogenase ,ADMET, absorption, distribution, metabolism, excretion and toxicity ,Risk analysis (engineering) ,BIOS, biology-oriented synthesis ,030220 oncology & carcinogenesis ,Structure-based simplification ,VANGL1, van-Gogh-like receptor protein 1 ,Pharmacophore-based simplification ,PD, pharmacodynamic ,SAR, structure‒activity relationship ,Structural simplification ,Drug ,media_common.quotation_subject ,TbLeuRS, T. brucei LeuRS ,PK, pharmacokinetic ,Drug design ,03 medical and health sciences ,MDR-TB, multidrug-resistant tuberculosis ,Lead (geology) ,SAHA, vorinostat ,aaRSs, aminoacyl-tRNA synthetases ,CCK, cholecystokinin receptor ,PKC, protein kinase C ,hA3 AR, human A3 adenosine receptor ,HLM, human liver microsome ,030304 developmental biology ,Lead optimization ,Reducing chiral centers ,NPM, nucleophosmin ,JAKs, Janus tyrosine kinases ,SCONP, structural classification of natural product ,lcsh:RM1-950 ,3D, three-dimensional ,MCRs, multicomponent reactions ,AM2, adrenomedullin-2 receptor ,lcsh:Therapeutics. Pharmacology ,HBV, hepatitis B virus ,LE, ligand efficiency ,Reducing rings number ,aa-AMS, aminoacylsulfa-moyladenosine ,NP, natural product - 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., Graphical abstract Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design. For large or complex lead compounds, structural simplification is helpful to discover drug-like molecules with improved synthetic accessibility and favorable pharmacodynamic/pharmacokinetic profiles.Image 1
- Published
- 2019
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