Structure-based drug design is one of the more successful approaches used in medicinal chemistry to design and develop new drugs. One approach in structure-based drug design is to use high performance computers for analysing proteins and designing new lead molecules. Among different computer-aided drug design approaches are comparative homology modelling of proteins and different ligand docking techniques, which are reviewed in Chapter 1. Some of these techniques have been applied to compounds that bind to G-protein coupled receptors and aspartic proteases. In Chapter 1, I have therefore discussed the importance of GPCRs and the use of homology modelling techniques, as well as the importance of aspartic proteases and their inhibitors.
Chapter 2 describes the putative binding of three different antagonists to the human complement-5 receptor (hC5aR), which is a GPCR on the surface of immune cells like neutrophils and macrophages. After developing a homology model structure of hC5aR, peptide-30 (N-methyl)-FKP(D-Cha)Wr, cyclic peptide-32 (AcF-[OP(D-Cha)WR]) and nonpeptide-33 (W54011) were docked into the receptor and putative binding sites were tested by mutations in the receptor. By linking the results of modelling with the effects of single receptor mutations on ligand affinity/antagonism, some insights have been provided for the binding sites on C5aR of these three antagonists.
Chapter 3 first develops a protocol for docking known ligands in one GPCR (NK2) to identify the putative receptor-binding location, and then validating the protocol using literature data for effects of site directed mutagenesis on ligand binding to the receptor. The optimised protocol was then applied to 16 different GPCRs, docking known ligands to identify putative binding site on each GPCR, and validating the putative ligand binding site using literature data for effects of site directed receptor mutations on ligand affinity/activity. The conclusion is that there is a common ligand binding site for all 17 different peptide activated GPCRs. The significance of this conclusion is discussed in relation to GPCRs and drug design.
Chapter 4 describes two modelling projects involving aspartic proteases. One project uses crystal structures of HIV-1 protease and its small molecule inhibitors to predict their potential binding to aspartic proteases of Plasmodium falciparum (human malarial parasite)