Pharmacological Screening: Drug Discovery

Traditionally, new treatments have been discovered through random testing of natural products, primarily parts/extracts of plants and herbs, on humans. Lately, new drugs were discovered by screening extracts from natural sources on animals, subsequently on humans. The testing of agents on living beings obviously is highly expensive and often involves ethical issues. This approach of screening compounds on living systems in modern terms is called phenotypic or physiology-based screening. In contrast to the traditional drug discovery, modern drug discovery (Mechanism-Based Approach) is facilitated with the advent of new screening technologies of miniaturization and automation of biological assays against a molecular target. As a result, high-throughput screening (HTS) platforms have been evolved to screen a large number of compounds typically in miniatured and automated biological assays. The basic premise of screening is that biological assays are reproducible, reliable, robust, and biologically relevant. The activities of HITs (initial actives or leads) in HTS platforms are typically confirmed in semi-manual/manual primary and secondary assays. Few selected leads further undergo iterative process of optimization for potency, selectivity, specificity, optimal absorption, distribution, metabolism and elimination (ADME) and pharmacokinetic (PK) properties. Compounds with desired potency in cellular assays and optimal drug metabolism and PK profile in animals are further screened in vivo animal models for efficacy. Compounds with the desired efficacy and safety (Advanced leads) undergo mechanistic and efficacy profiling studies in appropriate animal models and battery of regulatory toxicology studies. Advanced lead compound with optimal efficacy and safety data in toxicology studies is/are nominated as clinical candidate(s) for further development. The rigorous process of screening compounds and selecting clinical candidate(s) is tedious and resource consuming exercise but crucial for future success of molecule in human clinical trials.