Strategy of molecular drug design:pharmacophore and scaffold hopping
Zongru Guo · Zhongguo yaowu huaxue zazhi · 2008
Drug molecules are composed of scaffold and pharmacophore.The latter is an assembly of physico-chemical features and their spacial arrangement responsible for a specific activity.Discrete atoms,groups and/or fragments constitute pharmacophore,which incorporates with an integrated scaffold to form an ac- tual molecule.The same pharmacophore implanted on various scaffolds provides structurally diverse compounds that act on the same biological target.Based on the flexibility and plasticity of receptors,scaffolds can be rationally transformed,which leads to promiscuity.Promiscuity denotes the variability and diversity of receptor binding sites.The more promiscuity of the receptor,the more structural diversity the ligand molecule accommodates,which translates into more room for scaffold variation and higher success rate in drug discovery.In the evolution of hits to leads and the optimization of leads to drug candidates,the essence is to perform appropriate molecular operation,including preserving pharmacophore,varying scaffolds,and modifying functional groups and/or side chains,to convert organic compounds into medicines with safety,efficacy,stability and controllability.The strategies in scaffold alteration can be classified into three aspects: bio-isosterism,privileged structure-oriented,and scaffold hopping.The purpose is to improve physico-chemical properties,pharmacokinetic behaviors,and metabolic/chemical stability as well as to convey a structural novelty to compounds.This mini-review is to discuss the relationship between pharmacophore and scaffold and illustrate methods and skills in the scaffold hopping with some examples.