What is Rule of 3 drug discovery?

 The value of using the RO3 in FBDD is being (correctly) challenged4 as many useful fragment hits do not adhere to its restrictions (see the Practical Fragments blog website). We have always believed that the RO3 concept has limitations and, like other rules related to desirable physicochemical properties, such as the 'rule of five' guidelines5, it is simply a guideline that should not be overemphasized. Nevertheless, we believe that the RO3 has been useful in ensuring that fragment libraries really do consist of compounds with fragment-like properties, although reports of 'fragment' hits that actually resemble lead-like compounds — particularly considering their substantial molecular mass — do still appear.

The fundamental concept of fragment screening is to use simpler molecules so that the chemical space can be sampled much more efficiently than is possible when using molecules of greater complexity6. One consequence of screening smaller, simpler fragments is that their affinity is expected to be relatively low (>1 mM), given the limited numbers of potential interactions that they can make with the protein. Although weak in potency, fragment hits make high-quality interactions with the protein as they must overcome a substantial entropic barrier to binding, relative to their size. The detection of low-potency fragment hits presents substantial technical challenges, but to avoid these challenges and succumb to the temptation to screen larger, more complex molecules runs counter to the whole raison d'être of fragment screening.

For more details : Drug Discovery Conference

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