There is a significant pool of under-used NP fragments, and an immense number of novel NP fragment combinations are available to exploit to create NP-biased screening libraries and building blocks for use in lead optimisation. The design principles for PNP molecules have been laid out and are ready for exploitation by medicinal chemists. PNPs provide greater ring system novelty in the clinic and predictably distinctive physicochemical properties, especially increased nitrogenous aromatic rings, versus NonPNPs. However, it is our experience that recognising a PNP structure and knowing those NP fragment combinations that are non-biosynthetic, are often not intuitive or straightforward. Applying the available PNP algorithm in advance of synthesis is a necessary step. In designing new PNPs, synthetic challenges are likely to arise -the investment required needs to be balanced against the accumulating evidence supporting their biological relevance, clinical dominance and untapped potential. However, we note that nowadays thousands of PNPs have become available from commercial sources, such that PNP libraries can readily be established without extensive synthesis efforts. Further extension to consider additional NP ring systems and acyclic frameworks is also possible.