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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,

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                                                                                        5

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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