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Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO). The drug discovery process generally follows the following path that includes a hit to lead stage: * target validation (TV) → assay development → high-throughput screening → hit to lead (H2L) → lead optimization (LO) → preclinical drug development → clinical drug development The hit to lead stage starts with confirmation and evaluation of the initial screening hits and is followed by synthesis of analogs (hit expansion). Typically the initial screening hits display binding affinities for their biological target in the micromolar (10−6 molar concentration) range. Through limited H2L optimization, the affinities of the hits are often improved by several orders of magnitude to the nanomolar (10−9 M) range. The hits also undergo limited optimization to improve metabolic half life so that the compounds can be tested in animal models of disease and also to improve selectivity against other biological targets binding that may result in undesirable side effects. On average, only one in every 5,000 compounds that enters drug discovery to the stage of pre-clinical development becomes an approved drug. == Hit confirmation == After hits are identified from a high throughput screen, the hits are confirmed and evaluated using the following methods: * Confirmatory testing: compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS to make sure that the activity is reproducible. * Dose response curve: the compound is tested over a range of concentrations to determine the concentration that results in half maximal binding or activity (IC50 or EC50 value respectively). * Orthogonal testing: confirmed hits are assayed using a different assay which is usually closer to the target physiological condition or using a different technology. * Secondary screening: confirmed hits are tested in a functional cellular assay to determine efficacy. * Synthetic tractability: medicinal chemists evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or cost of goods. * Biophysical testing: nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), dynamic light scattering (DLS), surface plasmon resonance (SPR), dual polarisation interferometry (DPI), microscale thermophoresis (MST) are commonly used to assess whether the compound binds effectively to the target, the kinetics, thermodynamics, and stoichiometry of binding, any associated conformational change and to rule out promiscuous binding. * Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments. * Freedom to operate evaluation: hit structures are checked in specialized databases to determine if they are patentable. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Hit to lead」の詳細全文を読む スポンサード リンク
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