Computer-aided molecular design

Lead identification

Normally leads were discovered from natural products, biochemistry or exploring analogs of know substrates or ligands. Nowadays, computational methods are beginning to play a major role.

Only in the last few years: structure available during the drug discovery process. Membrane-bound proteins specially difficult to find.

Computer-aided drug design:

• Analog-based: uses pharmacophores (an explicit geometric hypothesis of the critical features of a ligand) and QSAR (quantitative structure-activity relationships), based solely on their chemical structure: the linear free energy principle.
• Structure-based: starting from the 3D-structure of the target (by X-ray crystallography, NMR spectrocopy, computer homology methods or ab initio methods), the binding site is located by comparison or homology. Conformational analysis: lowest energy conformations when free in solution and when bound to the receptor.

Two main approaches:

1. Docking: characterization of the ligand, sampling: positioning (configurational) and conformational states [FFT], and scoring: energetic evaluation of each discrete geometry.
   
2. De novo: construction of molecules that have not been synthesized previously. Three methods: a) fragment placement: focus on a small number of well-placed fragments, b) connection methods: the linker provides a compatible geometry for connecting the critical fragments, c) sequential growth: a step-by-step (starting with a seed) construction of a hypothetical ligand within a binding pocket.
   

Virtual screening: build a library to priorize experimental efforts.