Structural simplification: an efficient strategy in lead optimization

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.

Keywords: 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.