Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol

13C, 15N and 2H solid-state NMR spectroscopy have been used to rationalize arrangement and dynamics of solvent molecules in a set of isostructural solvates of droperidol. The solvent molecules are determined to be dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. 2H NMR spectra of deuterium-labelled samples allowed the characterization of the solvent molecule dynamics in the alcohol solvates and the non-stoichiometric hydrate. The likely motion of the alcohol molecules is rapid libration within a site, plus occasional exchange into an equivalent site related by the inversion symmetry, while the water molecules are more strongly disordered. DFT calculations strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent molecule

"Particle Informatics": Advancing Our Understanding of Particle Properties through Digital Design

We introduce a combination of existing and novel approaches to the assessment and prediction of particle properties intrinsic to the formulation and manufacture of pharmaceuticals. Naturally following on from established solid form informatics methods, we return to the drug lamotrigine, re-evaluating its context in the Cambridge Structural Database (CSD). We then apply predictive digital design tools built around the CSD-System suite of software, including Synthonic Engineering methods that focus on intermolecular interaction energies, to analyze and understand important particle properties and their effects on several key stages of pharmaceutical manufacturing. We present a new, robust workflow that brings these approaches together to build on the knowledge gained from each step and explain how this knowledge can be combined to provide resolutions at decision points encountered during formulation design and manufacturing processes

Studies of conformation and configuration using crystallographic methods

This Thesis demonstrates the use of the Cambridge Crystallographic Database for structure correlation studies in two very different fields. The first part of the Thesis (Chapters 2 and 3) is concerned with the systematic conformational analysis of medium-sized rings and satisfies the objectives of the study by: (i) applying novel classification techniques to the conformational descriptions of both the seven- and eight-membered rings, (ii) interpreting the results in terms of the relevant conformational hypersurface by locating the highly populated regions of that hypersurface and mapping the interconversion pathways, (iii) studying, modifying and improving the available methodologies for data analysis, and (iv) relating the conformational minima found using these methods to both the chemical environments of the fragments under investigation, and to energetic features of the hypersurface obtained by computational methods. The second major structure correlation experiment involves the analysis and description of 3-coordinated transition metal complexes using both simple geometrical models and group-theoretically based symmetry deformation coordinates. Non-bonded interactions will be seen to play a significant part in the geometry of the 3-coordinated fragment, and extrapolation of these results leads to the rationalisation of an addition/elimination scheme linking 4- and 2-coordinated fragments through the intermediate 3-coordinated species. Chapter 5 describes the crystallographic structure determinations of eight novel compounds: 3,5-cycloheptadienyl-3,5 dinitrobenzoate [C(_14)H(_12)O(_6)N(_2)]; a 34-membered diolide [C(_32)H(_60)O(_4)]; l-iodo-3-tosyloxy-propan-2-ane [C(_10)H(_11)O(_4)IS)]; 1β, 9 β -diacetyl- 7α-chloro-cis-hydrindane [C(_13)H(_19)O(_2)CI]; (R,R)-l,4-bis (2'-chloro-1 '-hydoxyethyl) benzene [C(_10)H(_12)O(_2)CI(_2)]; a fused penta-cyclic ring compound [C(_17)H(_14)]; 1,4 dibenzyl- 1,2,4,5-tetraazacyclohexane [C(_16) H(_20) N(_4)]; 1,5-di (2'-chloroacetoxy)-3,3-dimethyl-2,4- diphenyl-3-silapentane [C(_22)H(_26)O(_4) CI(_2) Si]

A first principles study of proton transport through model helical pores

Proton transport (PT) across cell membranes is a fundamental process and a key step in many biological functions, including cell signalling and enzymatic reactions. All biochemical reactions that convert energy from one form to another are mediated by PT, which also serves as a vital route to achieve cell pH stabilisation. The coding for membrane -bound proteins constitutes 25 -30% of all genes, and they are implicated in many diseases such as diabetes and Parkinson's. Consequently, they are the subject of major drug target studies (in fact the drug targets for all neurological diseases are membrane -bound proteins). Whilst PT is known to occur via transient water molecules across the cell membrane itself, it is more often the case that the mechanism involves proteins that span the membrane surface and act as proton- specific ion channels. PT has been widely studied in protein systems such as gramicidin A, cytochrome C oxidase, the M2 channel protein in the influenza A virus and bacteriorhodopsin. Evidence for the relay of H+ by buried water molecules ('water wires') mediated by the side -chains of alpha -helices have been substantiated in these and other proteins, but finding direct experimental evidence for the reaction pathway is extremely challenging work.When experiment can provide only partial answers, it is the role of computational modelling to complete the picture. Modelling these trans -membrane proteins at the full atomistic quantum mechanical level, however, lies beyond the capabilities of current computational techniques, necessitating the use of simplified models. To this end, work undertaken in this thesis has derived and tested a simplified model that is large enough to maintain the essential tertiary structures of transmembrane proteins, but small enough to permit full ab initio MD simulations over long time periods to be performed. The model is based on a single helix scaffold placed under periodic boundary conditions to create a cavity that supports a water wire. The simulations then focus on monitoring the behaviour of a proton as it 'hops' along this wire in a manner akin to the classical Grotthuss mechanism.Mechanistic studies have taken place using poly-glycine, poly-glycine-serine and poly-glycine-aspartic models, and show that the mechanism of PT in channel environments shares some features with the simulations reported for bulk water, with, e.g., the hydrogen bond distance shortening in the time period leading up to successful proton transfer. There are, however, also some important differences, such as the observation of a heightened number of proton rattling events. The channel environment also removes the need for the loss of a water molecule from the inner coordination sphere of the receiving water molecule as the constriction in space only allows a coordination sphere of three molecules, as opposed to four for bulk water.The effect of varying the density of water molecules in the channel has also been investigated. A range of cationic states have been identified, with widely varying lifetimes and compared across all models. We also observe that the helix plays an important role in directing the behaviour of the water wire: the most active proton transport regions of the water -wire are found in areas where the helix is most tightly coiled. Finally, we report on the effects of different DFT functionals to model a water - wire using the simplest poly -glycine model, and on the importance of including dispersion corrections to stabilize the helical structure.Finally, using the poly -glycine- aspartic acid model, a study was undertaken that focused on the direction of proton transport through the channel when the side chains of the aspartic acid residues interacted directly with the water wire. In this model there were two different pathways for the excess proton to pass along: a long hydrogen - bonded network of water molecules and amino acid residues, or a short [H30]+ diffusion pathway. It was found that the proton- hopping route over multiple water molecules and amino acid residues was preferred over the diffusion route, even though this pathway was substantially longer

Amine hydrochloride salts : a problem in polyurethane synthesis

A major problem encountered during the industrial synthesis of isocyanates, is the loss of amine starting material through reaction with the hydrogen chloride (HC1) by-product. HC1 is formed by the phosgenation of polymeric amines and also by the subsequent decomposition of the carbamyl chloride, Equation (1). HC1 readily reacts with the polymeric amine to form an unwanted and highly insoluble amine hydrochloride salt. (Fig. 3620) Methylene dianiline (MDA) and 4-benzylaniline (4-BA) were used as models for the industrial amine starting material with their hydrochloride counterparts methylene dianiline dihydrochloride (MDA.2HC1) and 4-benzylaniline hydrochloride (4-BA.HC1) as models for the industrial waste material. To understand the forces controlling the structure and stability of these solid amine hydrochloride salts the sold state structures of MDA, MDA.2HCl, methylene dianiline monohydrochloride (MDA.HCl), 4-BA and 4-BA.HCl were investigated using single crystal X-ray diffraction which led to the determination of their lattice energies. The XRD studies were also used as a basis for Density Functional Theory (DFT) calculations. The information obtained from the solid state structures, combined with an investigation of the solution phase behaviour of 4-BA.HCl(s), resulted in the determination of a kinetic model for the recovery of amine starting material. The proposed reaction scheme describes the conditions under which the dissociation of 4-BA.HCl(s) can occur. Reaction in a closed system shows no amine production while reaction in an open system permits, within solubility limits, the complete consumption of solid waste to produce free amine. From these two extremes the conversion of waste hydrochloride salt in the industrial reactor can be rationalised

A general mechanism for signal propagation in the nicotinic acetylcholine receptor family

Nicotinic acetylcholine receptors (nAChRs) modulate synaptic activity in the central nervous system. The α7 subtype, in particular, has attracted considerable interest in drug discovery as a target for several conditions, including Alzheimer’s disease and schizophrenia. Identifying agonist-induced structural changes underlying nAChR activation is fundamentally important for understanding biological function and rational drug design. Here, extensive equilibrium and nonequilibrium molecular dynamics simulations, enabled by cloud-based high-performance computing, reveal the molecular mechanism by which structural changes induced by agonist unbinding are transmitted within the human α7 nAChR. The simulations reveal the sequence of coupled structural changes involved in driving conformational change responsible for biological function. Comparison with simulations of the α4β2 nAChR subtype identifies features of the dynamical architecture common to both receptors, suggesting a general structural mechanism for signal propagation in this important family of receptors