ABSTRACT
Since ancient times the operation of the brain has elicited more than usual interest. Data mining of the human genome is revealing that many CNS abnormalities have a genetic component. As yet this information can not be used directly to cure or ameliorate specific CNS disorders although this is regarded as having great potential for future therapies. Current CNS drug design and 3D QSAR is based on knowing either the structures of key proteins and how smaller molecules interact with them to obtain a pharmacological response, or on hypothesising about key structural features and interactions by a variety of molecular modelling and computational techniques. Methods used include conformational analyses, pharmacophore development and QSAR which are now being actively applied to increase our understanding of how molecules interact with specific sites within the CNS as a basis for the design of new pharmacologically active compounds. In this review we give an overview of the latest strategies used in 3D-QSAR based drug design and survey the most recent applications of these strategies to the CNS. By way of example, accounts are given of computer-based research aimed at drugs targeting GABA, glutamate, dopamine and opioid receptors.
Subject(s)
Central Nervous System Agents/chemistry , Drug Design , Combinatorial Chemistry Techniques , Humans , Models, Molecular , Quantitative Structure-Activity RelationshipABSTRACT
The molecular radii (r) of a series of peptides have been determined by molecular modeling. With these data, it is shown that electrophoretic mobility (mu(ep)) is proportional to 1/r2, and that the dependence presented in textbooks (mu(ep) infinity 1/r) is wrong. Use of the approximately equivalent, mass-based Offord equation is discussed, and other relevant considerations are presented.
Subject(s)
Electrophoresis, Capillary/methods , Models, Chemical , Peptides/chemistry , Mathematics , Molecular Weight , Peptides/isolation & purificationABSTRACT
A molecular modeling package has been used to systematically hydrate a series of previously built peptides. The volume data derived have been used with the log-log form of the inverse square law and published electrophoretic mobilities to test for the most likely states of hydration. Starting with the bare peptides and increasing hydration, however, the strength of correlation diminishes, indicating that the average electromigrating peptide is not extensively hydrated. The shapes of the peptides are predominantly oblate ellipsoidal, but generally do not deviate significantly from spherical and progressive hydration increases this trend. Thus, shape correction does not play a significant role in the calculations.
