Common structural basis for central nervous system drug design

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

Immobilized artificial membrane chromatography : quantitative structure-retention relationships of structurally diverse drugs

The chromatographic capacity factors (log k‘) for 32 structurally diverse drugs were determined by high performance liquid chromatography (HPLC) on a stationary phase composed of phospholipids, the so-called immobilized artificial membrane (IAM). In addition, quantitative structure-retention relationships (QSRR) were developed in order to explain the dependence of retention on the chemical structure of the neutral, acidic, and basic drugs considered in this study. The obtained retention data were modeled by means of multiple regression analysis (MLR) and partial least squares (PLS) techniques. The structures of the compounds under study were characterized by means of calculated physicochemical properties and several nonempirical descriptors. For the carboxylic compounds included in the analysis, the obtained results suggest that the IAM-retention is governed by hydrophobicity factors followed by electronic effects due to polarizability in second place. Further, from the analysis of the results obtained of two developed quantitative structure-permeability studies for 20 miscellaneous carboxylic compounds, it may be concluded that the balance between polarizability and hydrophobic effects is not the same toward IAM phases and biological membranes. These results suggest that the IAM phases could not be a suitable model in assessing the acid-membrane interactions. However, it is not possible to generalize this observation, and further work in this area needs to be done to obtain a full understanding of the partitioning of carboxylic compounds in biological membranes. For the non-carboxylic compounds included in the analysis, this work shows that the hydrophobic factors are of prime importance for the IAM-retention of these compounds, while the specific polar interactions, such as electron pair donor−acceptor interactions and electrostatic interactions, are also involved, but they are not dominant.

Sequence-dependent structure/function relationships of catalytic peptide-enabled gold nanoparticles generated under ambient synthetic conditions

Peptide-enabled nanoparticle (NP) synthesis routes can create and/or assemble functional nanomaterials under environmentally friendly conditions, with properties dictated by complex interactions at the biotic/abiotic interface. Manipulation of this interface through sequence modification can provide the capability for material properties to be tailored to create enhanced materials for energy, catalysis, and sensing applications. Fully realizing the potential of these materials requires a comprehensive understanding of sequence-dependent structure/function relationships that is presently lacking. In this work, the atomic-scale structures of a series of peptide-capped Au NPs are determined using a combination of atomic pair distribution function analysis of high-energy X-ray diffraction data and advanced molecular dynamics (MD) simulations. The Au NPs produced with different peptide sequences exhibit varying degrees of catalytic activity for the exemplar reaction 4-nitrophenol reduction. The experimentally derived atomic-scale NP configurations reveal sequence-dependent differences in structural order at the NP surface. Replica exchange with solute-tempering MD simulations are then used to predict the morphology of the peptide overlayer on these Au NPs and identify factors determining the structure/catalytic properties relationship. We show that the amount of exposed Au surface, the underlying surface structural disorder, and the interaction strength of the peptide with the Au surface all influence catalytic performance. A simplified computational prediction of catalytic performance is developed that can potentially serve as a screening tool for future studies. Our approach provides a platform for broadening the analysis of catalytic peptide-enabled metallic NP systems, potentially allowing for the development of rational design rules for property enhancement.

Drug bioactivation, covalent binding to target proteins and toxicity relevance

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Electrospun single-walled carbon nanotube/polyvinyl alcohol composite nanofibers : structure-property relationships

Polyvinyl alcohol (PVA) nanofibers and single-walled carbon nanotube (SWNT)/PVA composite nanofibers have been produced by electrospinning. An apparent increase in the PVA crystallinity with a concomitant change in its main crystalline phase and a reduction in the crystalline domain size were observed in the SWNT/PVA composite nanofibers, indicating the occurrence of a SWNT-induced nucleation crystallization of the PVA phase. Both the pure PVA and SWNT/PVA composite nanofibers were subjected to the following post-electrospinning treatments: (i) soaking in methanol to increase the PVA crystallinity, and (ii) cross-linking with glutaric dialdehyde to control the PVA morphology. Effects of the PVA morphology on the tensile properties of the resultant electrospun nanofibers were examined. Dynamic mechanical thermal analyses of both pure PVA and SWNT/PVA composite electrospun nanofibers indicated that SWNT–polymer interaction facilitated the formation of crystalline domains, which can be further enhanced by soaking the nanofiber in methanol and/or cross-linking the polymer with glutaric dialdehyde.

Structure-property relationships of nylon 6, MXD6, their blends and nanocomposites

This research project aimed to develop an understanding of the structure-property relationships of nanocomposite materials (injection moulded and fibres) based on nylon 6, MXD6 and their blends, with a layered silicate in combination with polyhedral oligomeric silsesquioxane nanoparticles and SEBS rubber particles.

Effect of structure-property relationships on fatigue failure in natural fibres

The fatigue behaviour of natural fibres is important for fibre processing efficiency as well as the properties and performance of products made from these fibres. This chapter presents some fibre fatigue results obtained from various experimental methods and testing conditions. It demonstrates that many factors, including fibre structure and chemical treatments, affect the fatigue failure in natural fibres. Examples of controlling fibre fatigue life for different purposes are also presented. Knowledge of the fatigue behaviour of natural fibres will help product design and care.

Structure-property relationships in plasticized solid polymer electrolytes

The addition of various kinds of plasticizers can enhance the conductivity of polymer electrolyte systems, in some cases by many orders of magnitude. The plasticizer may be a low molecular weight solvent, or be a low molecular weight polymer. As the plasticizer concentration increases there is an inevitable deterioration in material properties. In this work we have investigated the effect of plasticizer on the conductivity, thermal properties and matrial properties of a number of systems including urethane cross-linked polyethers and polyacrylates. In some of the systems, in particular the polyether electrolytes, the plasticizer acts to enhance conduction by acting as a cosolvent for the salt as well as increasing chain flexibility. Its efficacy is dependent on its structure and characteristics as a solvent. Although T_g is lowered in a close to linear fashion with increasing plasticizer content and thereby conductivity increased rapidly, the elastic modulus changes more slowly. This reflects the coupling of conduction to the local mobility of the molecular units of the combined solvent system and the relative decoupling of the mobility and glass transition from the material properties. In these systems the latter are a function mainly of the longer range structure of the polymer network. The changes in conductivity and materials properties are interpreted in terms of a configurational entropy model of the solution.

The effect of alternate heating rates during cure on the structure-property relationships of epoxy/MMT clay nanocomposites

This paper investigates the effect of both the mixing technique and heating rate during cure on the dispersion of montmorillonite (MMT) clay in an epoxy resin. The combination of sonication and using a 10. °C/min heating rate during cure was found to facilitate the dispersion of nanoclay in epoxy resin. These processing conditions provided a synergistic effect, making it possible for polymer chains to penetrate in-between clay galleries and detach platelets from their agglomerates. As the degree of dispersion was enhanced, the flexural modulus and strength properties were found to decrease by 15% and 40%, respectively. This is thought to be due to individual platelets fracturing in the nanocomposite. Complementary techniques including X-ray diffraction (XRD), small angle X-ray scattering (SAXS), scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX), transmission electron microscopy (TEM) and optical microscopy were essential to fully characterise localised and spatial regions of the clay morphologies.