Drug discovery hit to lead

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Please improve this article if you can. (March 2007)

Early drug discovery involves several phases from target identification to preclinical development. The identification of small molecule modulators of protein function and the process of transforming these into high-content lead series are key activities in modern drug discovery. The Hit-to-Lead phase is usually the follow up of high-throughput screening (HTS). It includes the following steps:

1 Hit confirmation
2 Hit explosion
3 Lead generation phase
4 Lead optimization phase
5 See also
6 External links

[edit] Hit confirmation

The Hit confirmation phase will be performed during several weeks as follows:

re-testing: compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS.
Dose response curve generation: several compound concentrations are tested using the same assay, an IC50 or EC50 value is then generated
orthogonal testing: confirmed hit 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 assay or in a cellular environment. Membrane permeability is usually a critical parameter.
chemical amenability: medicinal chemists will evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or costs
Intellectual Property evaluation: Hit compound structures are quickly checked in specialized databases to define patentability
Biophysical testing: Nuclear magnetic resonance (NMR), Isothermal Titration Calorimetry, dynamic light scattering, surface plasmon resonance are commonly used to assess whether the compound binds effectively to the target, the stoïchiometry of binding and to identify promiscuous inhibitors.
Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments.

[edit] Hit explosion

Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests. An Ideal compound cluster will:

have compound members that exhibit a high afinity towards the target (less than 1 µM)
show chemical tractability
be free of Intellectual property
not interfere with the P450 enzymes nor with the P-glycoproteins
not bind to human serum albumin
be soluble in water(above 100 µM)
be stable
have a good druglikeness
exhibit cell membrane permeability
show significant biological activity in a cellular assay
does not exhibit cytotoxicity
not be metabolized rapidly
show selectivity versus other related targets

The project team will usually select between three and six compound series to be further explorated. The next step will allow to test analogous compounds to define Quantitative structure-activity relationship (QSAR). Analogs can be quickly selected from an internal library or purchased from commercially available sources. Medicinal chemists will also start synthetizing related compounds using different methods such as combinatorial chemistry, high-throughput chemistry or more classical organic chemistry synthesis.

[edit] Lead generation phase

The objective of this drug discovery phase is to synthesize lead compounds, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics. This optimization is accomplished through empirical modification of the hit structure and/or by employing structure-based design if structural information about the target is available.