Cadd And Modeling Anticonvulsant Drugs

Modern CADD calculations (particularly quantum mechanics calculations) are being used to study smaller molecules such as anticonvulsant drugs (Weaver, 1996; Carter et al., 2003). Unlike the molecular mechanics calculations on large receptor proteins, these drug molecule calculations are highly accurate, rivalling high quality experimental studies. This accuracy is exemplified by a recent study of tricyclic anticonvulsant drugs.

Tricyclic molecules are frequently used to treat a diversity of disorders. As their name implies, tricyclic drugs contain three rings, fused together. Molecules belonging to this structural class are routinely used for the treatment of epilepsy

FIGURE 3 1.2 Computer model of the GABA-A receptor protein. A computer model of the GABA-A receptor protein achieved using homology modeling in conjunction with molecular mechanics energy minimizations. The side-view (A) and top-view (B) of the protein are shown. Such theoretical models of protein structure have not yet reached the level of accuracy to permit rational drug design. (See Plate 25 in color plate section.)

FIGURE 3 1.2 Computer model of the GABA-A receptor protein. A computer model of the GABA-A receptor protein achieved using homology modeling in conjunction with molecular mechanics energy minimizations. The side-view (A) and top-view (B) of the protein are shown. Such theoretical models of protein structure have not yet reached the level of accuracy to permit rational drug design. (See Plate 25 in color plate section.)

(carbamazepine, oxcarbazepine) as well as psychosis (chlorpromazine), schizophrenia, depression (amitriptyline), headache, insomnia and chronic pain. In treating these many disorders, tricyclic drugs demonstrate an ability to bind to a plethora of different (and structurally quite distinct) receptors, including the voltage gated Na+ channel protein as well as multiple types of dopamine receptors, serotonin receptors and acetylcholine receptors.

The relationship between tricyclic structure and bioactivity can be assessed using CADD calculations. Employing quantum mechanics calculations, Marone et al. (1999) were able to quantify the spatial relationships ('butterfly angles') between the planes defined by the 'aromatic wings' of the tricyclic molecules. A series of angular descriptors can be used as measures of these spatial relationships; these descriptors can be accurately calculated using molecular orbital calculations. These angles and spatial relationships are shown in Figure 31.3. These high-level quantum mechanics calculations enable fundamental insights into the mechanism of action of anticonvulsant drugs.

Tricyclic Butterfly

FIGURE 3 1.3 Butterfly angles of a tricyclic drug. Many neuroactive drugs have a tricyclic structure. Some are anticonvulsants, while others are antidepressants or antipsychotics. The anticonvulsant tricyclics interact with the voltage gated Na channel protein. The angles formed between the various rings within these molecules define the receptor site with which the molecule interacts; these angles can be rigorously determined using quantum mechanics calculations.

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