How Are the Design Constraints Derived

For a putative drug molecule to compete effectively with the natural substrate at a given receptor, specific interactions with protein atoms in the receptor site must take place. These usually take the form of noncovalent interactions, the sura of which should be favorable enough to overcome the penalty incurred by steric repulsions, the freezing of transladonal and rotational degrees of freedom, desolvation, and other forces that would otherwise prevent binding.  

For the purpose of de novo design, one must translate those interactions into constraints that can be employed during molecular structure generation. 

Because the majority of de novo design programs are aimed at the structure-based design problem, where a suitably high resolution crystal structure of the receptor is available, we shall focus our discussion on this situation first. Constraints derived from other design scenarios, such as receptor models, pharmacophores, or CoMFA models, will be treated later. 

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