Drugs play an integral role in the battle against the many diseases afflicting humans. In order to fight this battle drugs are designed to enhance their disease-fighting properties. There are two major types of drug design. The first is referred to as structure-based drug design and the second is ligand-based drug design. Structure-based drug design relies on knowledge of the three-dimensional structure of the protein molecule target usually obtained by X-ray crystallography which enhances the ability to create novel drugs that combat disease. The detailed knowledge of the protein structure serves as a blueprint for the design of a lead compound. The lead compound is designed atom by atom optimizing both shape and charge complementarity with the active site of the protein target to enhance their interaction and suppress protein function (Fig. 1 illustrates the structural similarity between the lead compound and the enzyme’s active site). After the lead compound has been synthesized, scientists then use X-ray crystallography to analyze the structure of the protein target bound to the lead compound (Fig. 2 demonstrates the binary complex of a lead compound bound to the enzyme’s active site). The binary complex demonstrates how the compound binds the active site of the target protein. Using this structural information, redesigned lead compounds are then synthesized and further refined and analyzed in an iterative process until a sufficiently potent compound has been designed and optimized. Ligand-based drug design depends on information from all ligands that bind to the protein target. These ligands are utilized to generate a molecular framework describing all the critical elements responsible for ligand interaction with the protein target (Fig. 3 demonstrates all the ligand features essential for protein target interaction, such as the H-bond acceptor region). Incorporation of these elements into one ligand should augment protein-ligand interaction. Additionally, a protein target model is generated based on the composite ligand. This protein model is used to design additional ligands with features that improve interaction with this model. The classic target for rational drug design is the protein molecule functioning as an enzyme. Enzymes catalyze biochemical reactions by lowering the energy barrier from substrate to product. Occasionally a malfunctioning enzyme can cause disease. Rational drug design aims to create an extremely selective compound that will only bind to the active site of this malfunctioning enzyme, thereby preventing the defective enzyme’s function and ultimately halting progression of the disease.
