Drug discovery approaches

Fig. 3.1 Steps involved in drug discovery approach - a typical example. Joint efforts of classical genomics, proteomics, homology modelling, receptor- or structure-based screening approaches, and finally the structural biology efforts to determine the 3D structures of target reeeptor and receptor-ligand complex to get structural insight info their interactions...

Fig. 3.2 A more detailed example of the different steps involved in a classical drug discovery approach. Different steps, duration, and number of molecules involved are shown for comparison...

Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

Among the different drug discovery approaches explored in the past few years to modulate IGF-IR function, two of them—antagonistic antibodies and small molecular mass kinase inhibitors—represent, at this point in time, the... 

Severe, life-threatening diseases, such as cancer require a different drug discovery approach. Safety requirements in most oncology targets tolerate more side effects, which otherwise would severely limit the use of a medicine in other indications. For example, in addition to hair loss, a common side effect of cancer treatment, compounds which affect cell cycle, cell proliferation and apoptosis pathways also cause other serious side effects and make the patient endure severe adverse drug reactions (ADRs). 

Modern drug discovery approaches involve HTS, where, applying full automation and robotics, hundreds of molecules can be screened using several assays within a short time, and with very little amounts of compounds. In order to incorporate natural products in the modern HTS programmes, a natural product library (a collection of dereplicated natural products) needs to be built. Dereplication is the process by which one can eliminate recurrence or re-isolation of same or similar compounds from various extracts. A number of hyphenated techniques are used for dereplication, e.g. LC-PDA (liquid chromatography-photo-diode-array detector). 

Felder, E.R. and Poppinger, D. Combinatorial Compound Libraries for Enhanced Drug Discovery Approaches. Advances in DrugResearch, 1997,30,11 1-199. 

All drug-discovery approaches have so far been focused on blocking the lectin domain. Given that the role of the EGF and CR domains in ligand binding is still unclear [109], our structural considerations will concentrate exclusively on the lectin domain and the selectin ligands. 

This drug-discovery approach is addressed by a new area of pharmaceutical research known as prohling [2-5]. 

Levoye, A., and Jockers, R (2008) Alternative drug discovery approaches for orphan GPCRs. Drug Discov. Today 13, 52-58. 

In humans, 48 NR genes have been identified (Fig. 15.3-1) [1], A feature that unifies the NRs as a superfamily is that each receptor consists of an assembly of functional modules (Fig. 15.3-2) [2]. For the purpose of this review, the module most relevant to current drug discovery approaches is the C-terminal... 

The availability of the three-dimensional structure of the protein complex allows structure-driven drug discovery approaches. In this case, a pharmacophore model is first established. This corresponds to identifying the interactions that take place at the interface and which contribute most to AG. The importance of these interactions can be validated by site-directed mutagenesis or, when possible, by the use of peptides. Once these interactions are validated, molecules containing chemical groups mimicking these key interactions are selected from compound libraries and tested. Very often these initial molecules are not optimal (e.g., they do not make all the key contacts) and they must be modified to enhance their potency. This is done, for example. 

---