Pseudoreceptor modelling in drug design : Applications of Yak and PrGen

The pseudoreceptor modelling approach discussed in this chapter tries to take advantage of the receptor fitting methodologies applied in a direct drug-design scenario for property-based receptor mapping projects, indicative for indirect drug design. A major advantage of the techniques implemented in Yak and PrGen lies in the combination of an atomistic receptor model, being represented by a truncated protein-binding cleft, and a directional force field [61–63] that is capable of treating ligand-metal ion-protein interactions, frequently found to be of prime importance for the docking event in various pharmaceutically targeted receptors and enzymes. Expanding the precursor program Yak by including pharmacophore relaxation, equilibration, receptor-mediated pharmacophore alignment, correlation-coupled minimization and the options to explore ligand and receptor space by Monte Carlo simulations certainly accounts for a more realistic approach treating pharmacophore-receptor interactions by computational means. p From our experience, we strongly believe that atomistic models help to increase the apprehension of the structure-based drug-design approach by chemists, thereby facilitating the chemical realization of proposed compounds that emerged from modelling studies.

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