Initial screening, whether in silico or in vitro, frequently leads to best hits that are not good enough for the intended application - affinity too low, insufficient selectivity, insufficient stability, solubility, pharmacokinetics. Having an initial 3D-model of how the initial lead compound interacts with the drug target allows to elaborate derivative compounds that preserve the feature essential for the interaction, but improve specific properties, e.g. add hydrophilic groups in positions not essential for targeting to improve solubility, replace amide or ester groups subject to enzymatic cleavage to increase biological stability, rigidify the compound in the binding conformation or add additional interacting groups to improve affinity to the desired target and to reduce off-target interactions.

In order to achieve desired properties in our compound, we generate all possible analogs. It is possible that one of the analogs may have desired properties.

Two main reasons: 1) In QSAR studies we need to work within a series of similar compounds (homogeneous series) that assures a coherence (and thus the reliability) of the model. The assumption is that we DO NOT MODEL THE CHEMICO-BIOLOGICAL INTERACTION as such (an impossible task) but the (relatively small) variations linked to different substituents over a common theme (in pharmacological terms a pharmacophore represented by a lead compound).

In other words what assures the validity of the prediction is the presence of a unique (even if unknown) mechanusm of action with a single limiting step.

2) In practice, the great majority of compounds undergo chemical modifications when entering an organism (e.g. many drugs are administered as pro-drug expecting yhey are transformed into active compounds by enzymatic apparatus of the host).

Many reasons behind it

1) Improving the activity of compound towards the target disease

2)reducing toxicity of toxophores if present in a compound

3)improving chemical biological interactions

4)stereochemistry if present in a compound (DL, EZ) this also effect binding of drug to the protein

and many more reasons are there that are uncounted..