Drug Discovery Workflows

The Representative ADME/Tox Assays That Are Routinely Performed in Drug Discovery 

HERG channel inhibition Microsomal stability Metabolite identification Aqueous solubility Enzyme activity Permeability Cytotoxicity 

Metabolic drug-drug interactions Protein binding 

Multiple routes of administration Single or repeat dosing Daily clinical observation Histopathology 

Dose ranging Linearity Proportionality Toxicokinetics Biliary excretion Mass balance Tissue distribution Placental transfer Metabolite profiling Surgical models 

---

Bigure 16.5 summarizes our approach to using validated QSAR models for virtual screening as applied to the anticonvulsant dataset. It presents a practical example of the drug discovery workflow that can be generalized for any dataset in which sufficient data to develop reliable QSAR models is available. 

Fig. 16.5 Computer-aided drug discovery workflow based on combination of QSAR modeling and consensus database mining as applied to the discovery of novel anticonvulsants [10]. The workflow emphasizes the importance of model validation and applicability domain in ensuring high hit rates as a result of database mining with predictive QSAR models.

One early step in the workflow of the medicinal chemist is to computationally search for similar compounds to known actives that are either available in internal inventory or commercially available somewhere in the world, that is, to perform similarity and substructure searches on the worldwide databases of available compounds. It is in the interest of all drug discovery programs to develop a formal process to search for such compounds and place them into the bioassays for both lead generation and analog-based lead optimization. To this end, various similarity search algorithms (both 2D and 3D) should be implemented and delivered directly to the medicinal chemist. These algorithms often prove complementary to each other in terms of the chemical diversity of the resulted compounds [8]. 

Key words Drug discovery, chem-informatics, molecular design, combinatorial chemistry, combinatorial library, synthesis protocol, PGVL, reactant, product, enumeration, filtering integration, workflow, streamline, desktop tool, software deployment. 

Figure 5.16. The workflow used within ADEPT (A Daylight Enumeration and Profiling Tool GlaxoWellcome, UK) for compound selection and library design. [Reproduced from A. R. Leach and M. M. Hann, Drug Discovery Today 5, 326-336 (2000), with permission of Elsevier Science.]...

Rule-based systems are a part of a solution but do not constitute the entire solution. Problem solving in scientific areas is quite often part of a large workflow that incorporates dozens or hundreds of individual processes. A rule base is a part of an expert system, which itself is a part of an extensive process. Looking, for instance, at a drug discovery process, rule bases might be used to predict the docking behavior of a new molecule however, they would not be able to predict adverse reactions. 

Table 2.2 contains a list of ADME-PK assays that are routinely used to provide information via in vitro assays, lead optimization screens, and in vivo PK studies [22], Each assay is developed and applied with the intent of providing a quick survey of ADME-PK properties. Certainly, the workflow of drug discovery activities can often be depicted in a linear, stepwise fashion according to the ADME-PK screens highlighted in Table 2.2. However, such a workflow would not take into consideration the dynamics of a drug discovery program nor would such a workflow depict the differences that exist between different programs (i.e., diabetes, cancer, cardiovascular). The fact is that the discovery process is often initially supported with a standard set of ADME-PK assays that can be viewed as somewhat compulsory and highly iterative.

Despite the extensive use of ADME-PK screens in drug discovery, there is no one correct or standardized workflow for drug discovery. Often, ADME screening strategies are dictated by specific needs of the discovery program (i.e., therapeutic area, competitive landscape), recent precedent (i.e., success, failure), and/or the chemistry and disposition of a series of lead compounds. 

Since one of the fundamental requirements for crystallization is good solution properties, this type of screen can also be used to assess suitable solution conditions for crystallization trials. The application of the described workflow led to the successful expression and purification of several kinases, which are validated targets in drug discovery. Figure 15.2-5 shows a gallery of the corresponding spectra, which were recorded on the uniformly 15N-labeled proteins in our group. 

Integration of Automated Workflow in Chemoinformatics for Drug Discovery... 

---