Pharmacological activity of compounds(drugs) depend mainly on their interaction with biological matrices (drug targets), such as proteins (receptors, enzymes), nucleic acids (DNA and RNA) and biomembranes (phospholipids and glycolipids).
All these matrices have complex three-dimensional structures which are capable to recognize (bind) specifically the ligand (drug) molecule in only one of the many possible arrangements in the three-dimensional space. It is the three-dimensional structure of the drug target that determines which of the potential drug candidate molecules is bound within its cavity and with what affinity. This section of PHAR.331 concerns factors which control three-dimensional shape of organic molecules (drugs) viewed from the perspective of their interaction with potential biological targets.
The current trend in drug markets is a rapid increase of the sales of chiral drugs at the expense of the achiral ones. By the year 2000 chiral drugs, whether enantiomerically pure or sold as a racemic mixture, will dominate drug markets. It is therefore important to understand how drug chirality affects its interaction with drug targets and to be able to use proper nomenclature in describing the drugs themselves and the nature of forces responsible for those interactions.
| Levomoprolol/Levotensin | Dexfenfluramine/Isomeride |
| Levodropropizine/Levotuss | Ibuprofen/Serectil |
| Levofloxacin/Cravit | Barnidipine/Hypoca |
The importance of most factors affecting the 3D-shape of the drug and receptor molecules is illustrated on the example of the oligopeptide chain above. Such an oligopeptide is a linear molecule which is built by atoms separated from each other by a certain distance (bond length), endowed with a certain charge (due to bond polarity) or hydrophobicity (a property of repelling water), related to more distant sites in the molecules by a rotation angle about the single bond, and featuring more rigid fragments such as bonds with partial double bond characters. In addition, the orientation of the R group (amino acid side chain) is very important (chirality of the amino acid), as it determines the shape of the cavities lined with the oligopeptide chains. These factors are itemized below:
Therefore, the purpose of this course is to lay out the principles of such subtle factors of organic structures as configuration (orientation of the R group) and conformation (rotation about the single bond), which are most important in determining biological activity in compounds of the identical or analogous constitution. This is done through introduction of the nomenclature of stereochemistry, discussion of principles of stereochemistry, and illustration of these principles with examples of known drugs, and how drug chirality affects their mode of activity.
STRUCTURE is the complete arrangement of all the atoms of the molecule in space as determined by such methods as X-ray diffraction (as defined by Cartesian coordinates of all atoms). This terms is the broadest one and includes constitution (nature of atoms, their number, the type of bonds and manner in which they are linked together(connectivity)), conformation and configuration.
CONFORMATION is the spatial arrangement of atoms in the molecule of the given constitution and configuration. Conformation can be changed without changes in constitution and configuration by a rapid(?) rotation about single bonds and pyramidal inversion(?) at some centers.
CONFIGURATION is the spatial arrangement of atoms that distinguishes molecules of the same constitution (isomers), other than distinction due to differences in the conformation.
SYMMETRY is a regular occurrence of certain patterns within an
object or structure (at macro- or microscopic level). These patterns are
generated by the presence of symmetry elements such as
These elements are discussed in detail in the next section. In general, symmetry and chirality are antagonistic terms, i.e. symmetry removes chirality, although numerous cases exists where a limited degree of symmetry exists in chiral molecules.
CHIRALITY is a property of an object which is non-superimposable with its mirror image. Most objects in the environment are chiral. In chemistry this term applies to molecules, specific conformations of molecules, as well as to macros copic objects such as crystals. Chirality is removed if and object molecule acquires a plane of symmetry, or a center of symmetry. The molecule can remain chiral with a limited combination of symmetry axes.
ENANTIOMERS are molecules related to each other as a real object to its mirror image. Enantiomers are therefore related to each other through the reflection by the mirror plane, and are not superposable. Not all object/mirror-image pairs constitute enantiomers, but only those which are not superimposable after any rotation/translation of the whole object, or its mirror image. Enantiomeric relation does not bear the aspect of energy; the conformational isomers existing in the fast interconversion are still considered enantiomers. For the purpose of the determination whether two conformations are enantiomeric, they are considered to be rigid. The existence of enantiomers is usually (but not always) associated with at least one chiral center. Enantiomers have exactly the same energies, and therefore are not differentiated by physical measurements other than optical rotation (rotation of the plane of polarized light).
DIASTEREOMERS are any molecules which have an identical constitution, but are not related through the mirror reflection operation. Diastereomers could be compounds with two or more chiral centers, in which not all chiral centers have opposite configuration to a corresponding chiral centers in another molecule (the whole molecule would be the mirror image of the other and thus an enantiomer). Diastereomers do not have to possess chiral center(s), they only need to differ by a spatial difference not related to mirror reflection. Thus, diastereomers could be nonchiral cis/trans -isomers of cyclic or olefinic (alkene) compounds. Diastereomers and enantiomers are frequently jointly referred to as stereoisomers.
STEREOISOMERS: a combined term including enantiomers and diastereomers.
