Macromolecular targets

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

Beddell CR, editor. The design of drugs to macromolecular targets. Chichester John Wiley Sons, 1992. 

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

Fundamentally, FBDD is a general approach aimed at deriving high affinity ligands for macromolecular targets starting from low MW binders, which are usually identified by the use of the aforementioned biophysical techniques [1, 2, 7, 8]. 

Foloppe N, MacKerell AD (2000) All-atom empirical force field for nucleic acids I. Parameter optimization based on small molecule and condensed phase macromolecular target data. J Comput Chem 21 (2) 86-104... 

The mechanisms of most drugs involve binding of the drug to a receptor. A receptor may be any macromolecular target, but the most common receptors are proteins. These include membrane proteins, enzymes, transporters, and structural elements. Some of the main receptors of interest for psychopharmacology are receptors for neurotransmitters and hormones, which show a high degree of selectivity. 

Fig. 10.6 Concept of multitarget affinity specificity screening (MASS). Macromolecular targets (typically structured RNA constructs or proteins) in nondenaturing buffers are mixed in solution with a collection of potential ligands derived from natural product fractions, combinatorial libraries, or other diverse compound collections. The...

Lipophilicity is of prime importance in the design of drugs. Indeed, it controls many parameters such as absorption, biological barrier passage (and consequently transport into organs and cells), and also interaction with the macromolecular target (cf. Chapter 3). 

Figure 8.5 Macromolecular targets for drug design. The mammalian ceU contains numerous macromolecules including lipids, enzymatic proteins, non-enzymatic proteins, carbohydrates, nucleic acids, other heterocycles, and water. All of these molecules present important opportunities for drug design.

Design refers to the proposal of a structure in order to achieve the objectives of binding to a macromolecular target site (in the extreme case no ligand may be known), or to achieve the enhancement in potency, the selectivity, the safety and the delivery characteristics that are deemed necessary. 

---