Approachestoleadoptimization新加坡国立大学药物化学课件.docx

PAGE PAGE # Approaches to Lead Optimization 2006/2007 Learning Objectives: Optimization of lead structures lies at the heart of medicinal chemistry. In this topic, the approaches to optimizing lead structures are discussed, with the purpose of imparting, wherever possible, the reasons why these changes are made. Examples of how these approaches are applied to drug design are discussed. References: 1. Silverman RB: Chapter 2. 2. Foye ' s Principle of Medicinal Chemistry Chapter 2. A lead structure is defined as a compound that has shown acceptable levels of activity and selectivity in a pharmacological or biochemically relevant assay. However, there is always a need to improve on the lead structure so that it can fulfill the requirements for clinical usefulness. Thus the lead compound must be modified and these activities are collectively referred to as “ lead optimization or lead modification Lead optimization may be seen as a means of defining that part of the molecule that is involved in interacting with the biological target (enzyme or receptor). Drugs act by binding specifically to biomacromolecules. A specific and unique 3D structure of the drug molecule is a prerequisite for activity. The initial step in the formation of a drug-receptor complex is a recognition event. The receptor has to recognize whether an approaching molecule possesses the requisite features necessary for binding. These requisite features are broadly referred to as the pharmacophore. Pharmacophore : ensemble of steric and electronic features that is necessary to ensure the optimal interactions with a specific biological target structure and to trigger /block its biological response. It is an abstract concept that accounts for the common molecular interaction capacities of a group of compounds towards their target structure. The pharmacophore can be considered as the largest common denominator shared by a set of active molecules. The 3D structure of many receptors and enzymes remain unk