Macrocycles in Drug DiscoveryLearning from the Past for the Future

We have analyzed
FDA-approved macrocyclic drugs, clinical candidates,
and the recent literature to understand how macrocycles are used in
drug discovery. Current drugs are mainly used in infectious disease
and oncology, while oncology is the major indication for the clinical
candidates and in the literature Most macrocyclic drugs bind to targets
that have difficult to drug binding sites. Natural products have provided
80–90% of the drugs and clinical candidates, whereas macrocycles
in ChEMBL have less complex structures. Macrocycles usually reside
in the beyond the Rule of 5 chemical space, but 30–40% of the
drugs and clinical candidates are orally bioavailable. Simple bi-descriptor
models, i.e., HBD ≤ 7 in combination with either MW < 1000
Da or cLogP > 2.5, distinguished orals from parenterals and can
be
used as filters in design. We propose that recent breakthroughs in
conformational analysis and inspiration from natural products will
further improve the de novo design of macrocycles.