Structure-Activity Relationship & Computer-Aided Drug Design

Structure-Activity Relationship & Computer-Aided Drug Design

1. Definition & scope of the topic

• Structure-Activity Relationship (SAR) is the empirical and quantitative study of how changes in the chemical structure of a compound influence its biological activity against a target — i.e., how variations in scaffold and substituents alter potency, selectivity and other properties (G&G 14e Ch.1, p.8).
  • Operationally, SAR is generated by synthesising or purchasing a series of analogues of a hit and testing each against the target to build "a picture of how various changes in the chemical structure influence activity against the target (structure-activity relationships, or SAR) and other properties" (G&G 14e Ch.1, p.7–8).
  • In the drug-screening pipeline a Lead is formally defined as "a hit series exhibiting the Structure-Activity Relationship (SAR) and demonstrating activities both in vitro and in vivo" — so SAR is the bridge between an isolated hit and a developable lead (SK Gupta, Drug Screening Methods Ch.2, p.21).
• Computer-Aided Drug Design / Drug Discovery (CADD) is the use of computational (in-silico) methods — molecular simulation, docking, similarity searching, structure prediction and machine learning — to model the physical interactions of compounds with their protein targets and thereby design or prioritise tight-binding ligands (G&G 14e Ch.1, p.3–4, 9–12).
  • The term in silico denotes an experiment performed by computer, complementary to the more familiar in vivo and in vitro approaches (Medhi Ch.35, p.338).
  • CADD became practical from the 1980s onward, driven by two parallel advances: (i) the ability to determine high-resolution 3-D structures of proteins by X-ray crystallography (Hodgkin, Kendrew, Perutz), and (ii) the rapid rise of computer technology enabling data processing, visualisation of large structures and molecular simulation (G&G 14e Ch.1, p.4).
• The topic is two-faceted: SAR is the medicinal-chemistry / lead-optimisation side, while CADD is the computational engine that increasingly drives both ligand discovery and SAR interpretation. Both sit within the broader drug discovery / drug invention pipeline (G&G 14e Ch.1, p.3–4).
• Drug discovery vs drug invention — the phrase "drug discovery" fits compounds obtained from nature, but today most new drugs are totally new compounds, painstakingly optimised against many criteria through an interplay of design and experimentation; in that sense modern drugs are "more invented than discovered" (G&G 14e Ch.1, p.4).