Prototype drug molecules

A perusal of Table I makes clear the general conclusion that alkyl modification at the C-20 position of the VBL molecule is function sensitive for all and each of the three basic reactions of the drug with microtubules in vitro. If we begin the discussion with deoxydesethyl VBL (5) as the prototype compound for this series of congeners, we find that the 10-fold increase in the IC50 for microtubule assembly observed in our earlier work was accompanied by an eilteration in the structure of the assembled microtubules. As exemplified in Fig. 4a, there are opened areas along the length of the tubule, and in some cases the linear array of protofilaments... 

Chlorpromazine is the prototype molecule of the series of substituted phenothiazine psychotherapeutic compounds. Chlorpromazine is used for the symptomatic management of schizophrenia and active acute psychoses. The drug is also used for the prevention and treatment of nausea and vomiting, and for the relief of restlessness and apprehension before surgery [1,2]. 

The other major class of transporter protein is the carrier protein. A prototypic example of a carrier protein is the large neutral amino acid transporter. An important function of the LNAA transporter is to transport molecules across the blood-brain barrier. As discussed previously, most compounds cross the BBB by passive diffusion. However, the brain requires certain compounds that are incapable of freely diffusing across the BBB phenylalanine and glucose are two major examples of such compounds. The LNAA serves to carry phenylalanine across the BBB and into the central nervous system. Carrier proteins, such as the LNAA transporter, can be exploited in drug design. For example, highly polar molecules will not diffuse across the BBB. However, if the pharmacophore of this polar molecule is covalently bonded to another molecule which is a substrate for the LNAA, then it is possible that the pharmacophore will be delivered across the BBB by hitching a ride on the transported molecule. 

The concept of abnormal proteins in CJD may provide insights useful for drug design. The pioneering (and Nobel Prize winning) work of Prusiner has enabled the preliminary identification of prototype agents as therapies for CJD. Preliminary work identified two classes of compounds with therapeutic potential polysulphated molecules and tricyclic molecules (e.g., phenothiazines, aminoacridines). These compounds bind to PrP and endeavor to inhibit the PrP to PrP cascade of conformational change. 

The 3-amino-4,7-dihydroxy-coumarin moiety is a core unit of this family of compounds. The amino group of coumarin scaffold is further decorated with derivatives of pyrrole or benzoic acid moieties. Also, branched deoxysugar 5-C-methyl-L-rhamnose (noviose) is installed onto one of the hydroxyls of the coumarin. Clorobiocin 67 and novobiocin 68 can be considered prototypical aminocoumarins. These molecules are potent inhibitors of bacterial gyrase and topo-isomerase IV and 68 is used to treat human infections. Several works also showed that analogs of 68, in combination with other drugs, can improve the chemotherapy of certain tumors [121]. 

Monoamine oxidase (MAO) is a mitochondrial enzyme found in neural and other tissues, such as the gut and liver. In the neuron, MAO functions as a safety valve to oxidatively deaminate and inactivate any excess neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. Three MAO inhibitors are currently available for treatment of depression phenelzine [FEN el zeen], isocarboxazid [eye soe kar BOX a zid], and tranylcypromine [tran ill SIP roe meen] no one drug is a prototype. Use of MAO inhibitors is now limited because of the complicated dietary restrictions required of patients taking MAO inhibitors. 

A crystal structure of 30 was obtained to gain a better understanding of the structural differences responsible for selectivity. This information, when combined with the known crystal structures facilitated the development of a series of highly selective, small molecule inhibitors of TF/VIIa that were nonpeptidic and did not interact with the catalytic apparatus of the enzyme. Based on the key features of the TF/VIIa crystal structure, a series of six-membered heterocyclic cores were docked, which led to the pyrazinone scaffold 31 as a prototype inhibitor from which to start future small molecule stracture-based drug design (Figure Several hundred com-... 

---