Lead-like Compounds

Lead-like compounds have lower initial values for structural properties, allowing increases without becoming non-drug-like. The “hits” that serve as starting places for leads come from high-throughput screening, virtual screening, natural ligands, natural products, and the scientific literature. In the “hit-to-lead” phase, it is important to include properties in the workflow and goals for lead selection. In this evaluation process, some effective concepts have been emerging: lead-likeness, template conservation, triage, and fragment-based screening. The use of one or more of these concepts can increase the chances of success in discovering a strong lead-like structural foundation. Structure modifications during optimization are often added onto the lead template, thus retaining much of the original core structure of the lead. An emerging strategy in exploring for novel leads is termed as fragment-based screening. The well-studied lead-like criteria reinforce the principle that success in discovering drug-like clinical candidates is higher when starting with compounds that have structural properties with lower values, which allow the opportunity for structural modifications to enhance activity and selectivity without condemning the series to unacceptable pharmacokinetic performance.