Complexity, drug-receptor interaction

A classic example of where definitive experimental data necessitated refinement and extension of a model of drug-receptor interaction involved the discovery of constitutive receptor activity in GPCR systems. The state of the art model before this finding was the ternary complex model for GPCRs, a model that cannot accommodate ligand-independent (constitutive) receptor activity. 

In summary, we have described the complex process of building an in silico model for receptors using various computational tools in conjunction with experimental data. Ultimately, a successful model is one that holds up under rigorous experimental scrutiny and is capable of providing useful predictions for drug-receptor interactions. 

It is thus a higher form of molecular "behaviour than selective com-plexation alone and involves two stages of information input. Enzyme reactions are examples of such processes, as well as, for instance, drug-receptor interactions. Two substrates could, in principle, display very similar thermodynamic and kinetic complexation behaviour (no selection) but still only one of them may be able to undergo a specific reaction (because of geometrical differences, for instance) and thus be recognized. 

The functional significance of this drug-receptor interaction is that the receptor complex regulates the entrance of chloride into the postsynaptic cells. The increase in chloride conductance mediated by GABA is intensified by the benzodiazepines. This facilitation of GABA-induced chloride conductance results in greater hyperpolarization of these cells and therefore leads to diminished synaptic transmission. 

Drug-receptor interactions often involve CT complex formation. Examples include the reactions of antimalarials with their receptors and of some antibiotics that intercalate with DNA. The CT energy is proportional to the ionization potential of the donor and the electron affinity of the receptor, but is usually no higher than about 30 kJ/mol. 

As stated in Chapter 10, when the drug—receptor interaction involves feedback, the system becomes more complex. Hence, we will first present modeling and associated mathematical analysis of two typical processes. This will be followed by several examples involving drug pharmacodynamics organized around pharmacotherapy with drugs affecting the endocrine, central nervous, and cardiovascular systems. 

Since the ir value is constitutive, the stereospecific nature of hydro-phobic bonding for drug-receptor interactions can be delineated by regression analyses with the tt values of substituents separately for each position of the congeners. Thus, the substituent effect on the emulsin hydrolysis of substituted phenylglucosides has been nicely delineated by analyzing kinetic constants separately for meta and para isomers. The meta substituents play no hydrophobic role in the enzyme-substrate complex formation 24). 

In fact, the enzyme-inhibitor interaction in itself is a chain of complex processes for the inhibitor molecule, including a number of desolvations, collisions with nonspecific sites on the enzyme protein, and resolvations before reaching the specific inhibition site. The complexity is not at all less than those considered for the transport and drug-receptor interaction processes of cytokinins. The situation is analogous to that a set of every rational number between zero and one corresponds in a one-to-one... 

The entire drug discovery process, in particular at the cellular and animal level, has its own challenges [3] that contribute to the innovation deficif . It is thus imperative that computational tools deliver rapid and accurate models. At the molecular level, drug-receptor interactions continue to be too complex to provide failsafe in silico predictions [4] Entropy and the dielectric constant are but two examples of properties still under debate. The challenges of in silico drug discovery include the evaluation of multiple binding modes, accessible conformational... 

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