The tools required at various points along the drug discovery process differ as we move from early hits to preclinical candidates. For example, during early-stage programmes, we frequently have to sift through large volumes of high-throughput screening (HTS) data; here, we require end-user-friendly high-throughput tools to help the ranking of hit families and the flagging of potential absorption, distribution, metabolism, excretion and toxicity (ADMET) liabilities within chemical series.
BIOTECHNOLOGY INTEGRATED ADMET TECHNOLOGIES IN DRUG DISCOVERY The ability to successfully decide which drug candidates to develop is fast becoming a much sought-after skill. evotec’s approach of combining a variety of in silico, T in vitro and in vivo technologies can help this decision-making process. he ability to successfully decide which have assembled and developed an integrated suite of drug candidates to develop is fast technologies to facilitate such decision-making, thereby becoming a much sought-after skill. leading to a more efficient and effective progression Evotec’s approach of combining a of preclinical development drug candidates within our variety of in silico, in vitro and in vivo drug discovery programmes. technologies can help this decision-making process. The tools required at various points along the drug “Fail fast, fail early” is a mantra often recited in discovery process differ as we move from early hits to today’s pharmaceutical and biotechnology industries. preclinical candidates. For example, during early-stage Escalating drug discovery and development costs programmes, we frequently have to sift through large plus the need to promptly accelerate potential volumes of high-throughput screening (HTS) data; here, new therapies to market within challenging we require end-user-friendly high-throughput tools timelines means that quick and iterative selection to help the ranking of hit families and the flagging of of the best possible drug candidates becomes a key potential absorption, distribution, metabolism, excretion rate-determining activity.1,2 The cost of late-stage and toxicity (ADMET) liabilities within chemical failures can be astronomical, so rapid elimination of series. As we progress through lead optimization, the least promising drug candidates throughout the increasingly sophisticated predictive in silico and preclinical drug discovery phase is essential. in vitro ADMET tools are required to facilitate the To select the most productive path through design of improved compounds with reduced ADMET preclinical drug discovery, the drug discovery team liabilities.3 As projects move towards the clinic, we want needs help to limit the number of medicinal chemistry to identify ADMET issues using in vivo evaluations, blind-alleys explored during prioritization and where possible, that adhere to the “3Rs” (replacement, refinement of drug candidates to a more optimal balance refinement and reduction) ethical framework. We have of on-target activity, physicochemical properties and assembled an integrated and complementary suite of pharmacokinetic-pharmacodynamic profiles. We in silico, in vitro and in vivo ADMET technologies using Evotec’s computational chemistry, in vitro ADMET and zebrafish larvae testing platforms. early-Stage technologies The first level of control of these physicochemical properties comes during the creation of the HTS compound library. Medicinal chemists design novel scaffolds, which are enumerated in multimillion compound virtual libraries. Drug-likeness filters (and similarity filters) — Lipinski-type and toxicophore rules — are applied, and only the best few hundred compounds are synthesized and added to the library. This library enhancement process is an ongoing activity, aimed at providing start points for medicinal chemistry that are least likely to present serious ADMET problems later. To maintain the control of these physicochemical properties, our chemists use in silico tools to calculate/predict the nature of compounds proposed March/April 2010 www.pharma-mag.com 5 BIOTECHNOLOGY Figure 1: Quantitative ESMA is only a front-line tool as it contains structure-activity relationship- generalized molecular models. As a programme based tools embedded into progresses into the later stages of hit-to-lead, a desktop tool — ESMA alongside the in vitro and in vivo assays that will (EVOseek Searching and Modelling Application).
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