Synthetic tractability: medicinal chemists evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or cost of goods.Secondary screening: confirmed hits are tested in a functional cellular assay to determine efficacy.Orthogonal testing: confirmed hits are assayed using a different assay which is usually closer to the target physiological condition or using a different technology.Dose response curve: the compound is tested over a range of concentrations to determine the concentration that results in half maximal binding or activity ( IC 50 or EC 50 value respectively).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.Hit confirmation Īfter hits are identified from a high throughput screen, the hits are confirmed and evaluated using the following methods: On average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug. 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. Through limited H2L optimization, the affinities of the hits are often improved by several orders of magnitude to the nanomolar (10 −9 M) range. Typically the initial screening hits display binding affinities for their biological target in the micromolar (10 −6 molar concentration) range. The hit to lead stage starts with confirmation and evaluation of the initial screening hits and is followed by synthesis of analogs (hit expansion). Target validation (TV) → Assay development → High-throughput screening (HTS) → Hit to lead (H2L) → Lead optimization (LO) → Preclinical development → Clinical development.The drug discovery process generally follows the following path that includes a hit to lead stage: These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO). 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.
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