Dynamic combinatorial chemistry (DCC) is a novel approach to medicinal chemistry which integrates the synthesis and screening of small molecule libraries into a single step. The concept uses reversible chemical reactions to present a dynamic library of candidate structures to a template which selects and removes the best binder from equilibrium. Using this evolutionary process with a biopolymer template, such as a protein, leads to the protein directing the synthesis of its own best ligand. Biological DCC applications are extremely challenging since the thermodynamic criterion of reversibility has to be met under physiological conditions to ensure stability of the biomolecular template. The list of reversible reactions satisfying these stringent criteria is limited and is a major constraint on achieving both reaction and structural diversity in adaptive dynamic libraries. This thesis reports the development of a catalysed version of acylhydrazone dynamic libraries which are truly adaptive under protein-friendly conditions. In the presence of aniline as a trans-imination catalyst, acylhydrazone dynamic combinatorial libraries equilibrate rapidly at pH 6.2 and are switched off by an increase in pH. We designed acylhydrazone libraries targeting the enzyme superfamily Glutathione-S-Transferase (GST) using a scaffold aldehyde, 4-chloro-3-nitrobenzaldehyde, which is structurally related to a known GST substrate chlorodinitrobenzene. On interfacing these dynamic libraries with two different GST enzymes (SjGST from the helminth worm Schistosoma japonicum and hGSTP1-1, a human isoform and an important oncology drug target) we observed isoformselective amplification effects with two different acylhydrazones selected by the proteins. To explore the potential of anchoring in our DCC methodology we conjugated the endogenous GST ligand, glutathione (GSH) onto the scaffold chloronitrobenzaldehyde. The GSH recognition motif acts as an anchor and allows us to explore the hydrophobic binding site of the enzyme in a fragment-based approach. The presence of the glutathione moiety led to increased solubility of the library members and a DCC experiment with the enzymes led to the selection of conjugate hydrazones with significant binding ability. Multi-level dynamic libraries use multiple exchange processes in the same system to increase their accessible structural diversity. These exchange reactions may be orthogonal, where the different chemistries can be activated or deactivated independently of each other, or simultaneous, where all the processes are dynamic and crossover under the same conditions. Together, these interacting molecular networks provide an exciting experimental approach to the emerging field of systems chemistry. We demonstrate that two reversible reactions, conjugate addition of thiols to enones and hydrazone formation, are fully compatible and orthogonal to one another in a single dynamic library. Hydrazone exchange takes place at acidic pH, while conjugate addition operates at basic pH. Simple pH change can be used to switch between each process and establish two channels of reactivity.

In semiconductor manufacturing, automated material handling systems (AMHSs) transport wafers through a complex re-entrant manufacturing process. In some systems, Overhead Hoist Transport (OHT) vehicles move throughout the facility on a ceiling-mounted track system, delivering wafers to machines and storage locations. To improve efficiency in such systems, this thesis proposes an adaptive dynamic routing approach that allows the system to self-regulate, reducing steady-state travel times by 4-6% and avoiding excessive congestion and deadlock. Our approach allows vehicles to be rerouted while in progress in response to changes in the location and severity of congestion as measured by edge traversal time estimates updated via exponential smoothing. Our proposed method is efficient enough to be used in a large system where several routing decisions are made each second. We also consider how the effectiveness of a AMHS layout differs between static and dynamic routing. We demonstrate that dynamic routing significantly reduces sensitivity to shortcut placement and allows an eight-fold increase in the number of shortcuts along the center loop. This reduces travel times by an additional 24%. To demonstrate the effectiveness of our proposed routing approach, we use a high-fidelity simulation of vehicle movement. To test the impact of routing methods on layout effectiveness, we developed an associated Excel-based automated layout generation tool that allows the efficient generation of thousands of candidate layouts. The user selects from among a set of modular templates to create a design and all simulation files are generated with the click of a button.

The main challenge faced by a dynamic compilation system is to detect and translate frequently executed program regions into highly efficient native code as fast as possible. To efficiently reduce dynamic compilation latency, a dynamic compilation system must improve its workload throughput, i.e. compile more application hotspots per time. As time for dynamic compilation adds to the overall execution time, the dynamic compiler is often decoupled and operates in a separate thread independent from the main execution loop to reduce the overhead of dynamic compilation. This thesis proposes innovative techniques aimed at effectively speeding up dynamic compilation. The first contribution is a generalised region recording scheme optimised for program representations that require dynamic code discovery (e.g. binary program representations). The second contribution reduces dynamic compilation cost by incrementally compiling several hot regions in a concurrent and parallel task farm. Altogether the combination of generalised light-weight code discovery, large translation units, dynamic work scheduling, and concurrent and parallel dynamic compilation ensures timely and efficient processing of compilation workloads. Compared to state-of-the-art dynamic compilation approaches, speedups of up to 2.08 are demonstrated for industry standard benchmarks such as BioPerf, Spec Cpu 2006, and Eembc. Next, innovative applications of the proposed dynamic compilation scheme to speed up architectural and micro-architectural performance modelling are demonstrated. The main contribution in this context is to exploit runtime information to dynamically generate optimised code that accurately models architectural and micro-architectural components. Consequently, compilation units are larger and more complex resulting in increased compilation latencies. Large and complex compilation units present an ideal use case for our concurrent and parallel dynamic compilation infrastructure. We demonstrate that our novel micro-architectural performance modelling is faster than state-of-the-art Fpga-based simulation, whilst providing the same level of accuracy.

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Optimization has been an active area of research for several decades. As many real-world optimization problems become increasingly complex, better optimization algorithms are always needed. Unconstrained optimization problems can be formulated as a D-dimensional minimization problem as follows: Min f (x) x=[x1+x2+……..xD] where D is the number of the parameters to be optimized. subjected to: Gi(x) <=0, i=1…q Hj(x) =0, j=q+1,……m Xε [Xmin, Xmax]D, q is the number of inequality constraints and m-q is the number of equality constraints. The particle swarm optimizer (PSO) is a relatively new technique. Particle swarm optimizer (PSO), introduced by Kennedy and Eberhart in 1995, [1] emulates flocking behavior of birds to solve the optimization problems. / In this paper the concept of dynamic particle swarm optimization is introduced. The dynamic PSO is different from the existing PSO’s and some local version of PSO in terms of swarm size and topology. Experiment conducted for benchmark functions of single objective optimization problem, which shows the better performance rather the basic PSO. The paper also contains the comparative analysis for Simple PSO and Dynamic PSO which shows the better result for dynamic PSO rather than simple PSO.

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