PLP inhibitors and dug design and drug action

inhibitors of PLP-containing coenzymes

many of these work by misdirection of electron density in the anionic intermediate to make a reaction intermediate, which hopefully undergo reaction with an active site residue

what side affecft did vigabatrin have

permenant retinal damage

polyamines

spermidine and spermine and the precursor putrescine are important regulators of cell growth, division, differentiation, required for DNA synthesis

PLP inhibitor effects on alanine, GABA, and orthine

put a chlorine, put a vinyl, and put in a L.G

inhibition of ornithine decarboxylase

lead to an antitumor/antimicrobial agents. causes alomst complete reduction in putrescine and spermidine, but slight effect on spermine- inducing an increases in SAM decarboxylase (elfornithine)

medicinal chemistry

the science that deals with the discovery or design of new potential therapeutic agents and their development into useful medicines (synthesis, structure-activity relationships, receptors interactions, absorption, distribution, metabolism, and excretion (ADME) and toxicology)

medicines

substances used to treat diseases

drugs

molecules used as medicines or as components in medicines

drug discovery

concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization. also in vivo proof of concepts in animals and concomitant demonstration of therapeutic index

drug development

begins when the decision is made to put a molecule into phase I clincal trials

how drugs are discovered if not directly?

a lead compound is identified

lead compound

prototype having desired activity but also undesirable characteristics (toxicity, other activities, insolubility, metabolism problems, oral bioavilability)

lead modified by synthesis

to amplify desired activity and minimize or elimiante undesirable properties

example of a drug discovery without a lead

penicillins and librium

lead discovery

first a bioassay (or screen) is needed. means to determine in vitro or in vivo relative to a control whether the compound has the desired activity and relative potency (ex antibacterial effect and strength of the effect)

bioassay selection

identify the types of biological properties the sought after compound should

phenotype vs. target

target-based drug discovery trends to rely upon in vitro testing for lead optimization and phenotype-based drug discovery leans upon in cellulo and in vivo testing (blended is preferred)

blended approach

starts with an observed effect in vivo and the discovery group seeks out the target responsible for the biological activity. once target is known, a molecular biology group will attempt to develop a biochemical binding assay to test the ability of a molecule to bind the target

high-throughput screens (HTS)

very rapid, sensitive in vitro screens, increase in number of hits (compounds that elicit a predetermined level of activity)

finding a lead compound-isolation of metabolic productions

the drugs used may themselves be inactive but are metabolized to active compounds (acetanilide is metabolized to acetaminophen (tylenol)

finding a lead compound- discovered from one indication

often molecules are discovered/synthesized for one indication and then turn out to be useful for others (tamoxifen, salvarsan, and interferon-alpha)

finding a lead compound- natural products

drugs can be derived from substances synthesized plants and animals ( bishydroxycoumarin a natural anticoagulant lef to the synthesis of warfarin)

fragement-based drug design (FBDD)

two weak fragments that bind in adjacent subsites may be linked to form one stronger ligand

why linking can work

preserves favorable contacts from both fragments, reduced cost of independently positioning two molecules, and can produce a large gain in affinity from two weak binders

why linking often fails

one or both fragments no longer bind in the orginal pose, linker length or geometry is wrong, conformational strain is introduced, steric clashes or desolvation penalties offset the expected gain