The Classical Search for Lead Structures

The starting point in the search for a new drug is a lead structure. Natural products found in plants, animals and micro-organisms are the source of many active ingredients. Their mode of action has been copied as the active principle for drug development. Endogenous substances such as hormones and neurotransmitters have also been investigated. Only a few natural products have become drugs themselves. In most cases, targeted chemical variations are required to optimize a lead compound for metabolic stability, half-life, or selectivity to make it ready for therapeutic use. Plants contain many valuable therapeutic compounds. They have usually evolved as effective defense mechanisms against all kinds of enemies. Nature offers a vast array of structural variations, but ambitious programs to elucidate the mechanisms of action of traditional medicines all too often result in the isolation of toxins and the discovery of already known principles. Animals have evolved toxins as an aggressive or defensive mechanism to be used against predators or enemies. They are usually proteins, peptides, or alkaloids that either kill or paralyze a victim. Snake venoms have served as a reference for the development of antihypertensive drugs and anticoagulants derived from leeches and bats. Genetic engineering is used to produce proteins for replacement therapy (e.g., insulin or erythropoietin). Microorganisms have been the source of lead compounds for antibiotics, but they usually require optimization for oral availability, broad-spectrum activity, and metabolic stability. Dyes and many synthetic intermediates produced in the chemical industry have been screened for biological activity and have provided important classes of compounds, such as the sulfonamides. Enzyme substrates, neurotransmitters, and hormones have been transformed into successful drugs by small but essential structural changes to endogenous ligands. Many drugs originated from clinical observations of side effects in practice, for example the antidiabetic effect of sulfonylureas from observing the side effects of sulfonamides. Today, huge libraries of compounds from plant extracts, microbial fermentations, and libraries of synthetically produced compounds are screened to utilize all possible resources for lead discovery. https://sn.pub/keziu0