Screen For The Target Or Adme First

Most commercial combinatorial libraries, some of which are very large and may be diverse, have a very small proportion of drug-like molecules [1]. Should only the small drug-like fraction be used to test against the targets? The industry's current answer is ''No.'' The existing practice is to screen for the receptor activity before ''drug-likeness.'' The reasoning is that structural features in molecules rejected for poor ADME properties may be critical to biological activity related to the target. It is believed that active molecules with liabilities can be modified later by medicinal chemists, with minimal compromise to potency. Lipinski [1] suggests that the order of testing may change in the near future, for economic reasons. When a truly new biological therapeutic target is examined, nothing may be known about the structural requirements for ligand binding to the target. Screening may start as more or less a random process. A library of compounds is tested for activity. Computational models are constructed on the basis of the results, and the process is repeated with newly synthesized molecules, perhaps many times, before satisfactory hits are revealed. With large numbers of molecules, the process can be very costly. If the company's library is first screened for ADME properties, that screening is done only once. The same molecules may be recycled against existing or future targets many times, with knowledge of drug-likeness to fine-tune the optimization process. If some of the molecules with very poor ADME properties are judiciously filtered out, the biological activity testing process would be less costly. But the order of testing (activity vs. ADME) is likely to continue to be the subject of future debates [1].

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