An overview of compound properties, multiparameter optimization, and computational drug design methods for PARP-1...

Breast cancer treatment with PARP-1 inhibitors remains challenging due to emerging toxicities, drug resistance, and unaffordable costs of treatment options. How do we invent strategies to design better anti-cancer drugs? A part of the answer is in optimized compound properties, desirability functions, and modern computational drug design methods that drive selectivity and toxicity and have not been reviewed for PARP-1 inhibitors. Nonetheless, comparisons of these compound properties for PARP-1 inhibitors are not available in the literature. In this review, we analyze the physchem, PKPD space to identify inherent desirability functions characteristic of approved drugs that can be valuable for the design of better candidates. Recent literature utilizing ligand, structure-based drug design strategies and matched molecular pair analysis (MMPA) for the discovery of novel PARP-1 inhibitors are also reviewed. Thus, this perspective provides valuable insights into the medchem and multiparameter optimization of PARP-1 inhibitors that might be useful to other medicinal chemists.