Hit/Lead Discovery

This chapter reviews some common practices in irrational drug design (serendipity), natural products, high through-put screening (HTS), fragment-based lead discovery, and DNA-encoded library. In the context of drug discovery in general, and medicinal chemistry in particular, penicillin G (1) is considered a hit/lead compound for all other β-lactamase inhibitors to follow. When Barnett Rosenberg discovered cisplatin (Platinol, 3) as a cancer chemotherapy in 1967, it may be considered as a hit/lead for later platinum-containing chemotherapeutics. Since cisplatin (3) is plagued by kidney toxicities, its modification led to carboplatin (Paraplatin, 4), which has much lower nephrotoxicity. Eventually, oxaliplatin (Eloxatin, 5) was approved in 1996, and it is devoid of nephrotoxicity. In the early 1990s, the pharmaceutical companies realized that there was too much at stake to leave to the chances for drug discovery. HTS emerged as a consequence of molecular biology revolution that led to the identification of many drug targets.