In early drug discovery, hit identification is the disciplined search for molecules that measurably affect a biological target or disease-relevant system, while lead compound selection is the subsequent decision to elevate the best validated “hits” into lead compounds that are strong enough—scientifically and operationally—to justify an optimization campaign. This “hit-to-lead” logic sits between assay development/high-throughput screening and full lead optimization, and its quality strongly influences downstream success. 1) Core Definitions (so the team argues less) What is a “Hit”? A hit is an initial compound (or series) that shows reproducible activity in a primary screen and survives basic confirmation steps. Hits often begin with modest potency (commonly micromolar range) and uncertain mechanism until validated. What is a “Lead Compound”? A lead compound is a more mature chemical starting point: typically a hit-derived molecule (or series) with improved potency and enough evidence for selectivity, developability, and tractable chemistry to justify systematic optimization toward a clinical candidate. Lead optimization then focuses on balancing potency with ADMET (absorption, distribution, metabolism, excretion, toxicity) and related properties. 2) Why Hit Identification Is Harder Than “Finding Actives” Modern discovery can generate many actives quickly, but the bottleneck is identifying…
