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From Structure Based to Systems Based Drug Design

By Luhua Lai
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China

Structural based drug design has been widely used in drug discovery for leading compounds identification and optimization. Many successful applications have been reported. Various docking methods and de novo structural based drug design programs have been developed, which were all developed based on the single target binding assumption. However, drugs encounter complicated situations and a huge number of biological molecules in the human body and may cause unexpected deleterious or beneficial effects. In order to understand mechanism of drug action, disease related molecular networks need to be studied. My group has been working on the human inflammation related arachidonic acid (AA) metabolic network in order to understand its regulation mechanism and to discover better intervention strategy. We developed a multiple target optimum intervention method (MTOI) that can be used to identify key targets for drug design and to predict optimum solutions to modulate disease network with minimum side effects. Systems based network analysis prompts new directions for structure based drug design, including: (1) multiple target drug design; (2) allosteric regulating, especially activatingmolecule design; (3) rational design of binding kinetics; (4) ligand design targeting intrinsically disordered proteins, etc. The disease network models can also be used to understand traditional Chinese medicine. A few examples of how systems analysis helps to discover efficient disease intervention strategies will also be given.