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Target validation (TV) → Assay development → High-throughput screening (HTS) → Hit to lead (H2L) → Lead optimization (LO) → Preclinical development → Clinical 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).
Target validation normally requires the determination that the target is expressed in the disease-relevant cells/tissues, [6] it can be directly modulated by a drug or drug-like molecule with adequate potency in biochemical assay, [7] and that target modulation in cell and/or animal models ameliorates the relevant disease phenotype. [8]
Northwestern University's High Throughput Analysis Laboratory supports target identification, validation, assay development, and compound screening. The non-profit Sanford Burnham Prebys Medical Discovery Institute also has a long-standing HTS facility in the Conrad Prebys Center for Chemical Genomics which was part of the MLPCN.
An example target identification by chromatographic co-elution (TICC) workflow. Drug-spiked lysate is fractionated using ion exchange chromatography. Fractions are collected every minute, then analyzed for both drug and protein content using LC-MS/MS. Drug and protein elution profiles are constructed and correlated. Target identification is ...
This approach is known as "reverse pharmacology" or "target based drug discovery" (TDD). [5] However recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening [ 6 ] which has led to a resurgence of interest in this method.
Druggability is a term used in drug discovery to describe a biological target (such as a protein) that is known to or is predicted to bind with high affinity to a drug. Furthermore, by definition, the binding of the drug to a druggable target must alter the function of the target with a therapeutic benefit to the patient.
Target identification provides resources important for searching drug targets with information on genome annotation, proteome annotation, potential targets, and protein structure. Virtual screening compiles resources important for virtual screening as QSAR techniques, docking QSAR, cheminformatics, and siRNA/miRNA.
Drug Discovery Today is a monthly peer-reviewed scientific journal that is published by Elsevier.It was established in 1996 and publishes reviews on all aspects of preclinical drug discovery from target identification and validation through hit identification, lead identification and optimisation, to candidate selection.