Povezivanje heterogenih prekrivajućih mreža: definicija, formalizacija i primene

This Ph.D. thesis addresses topics related to overlay networks, their de_nition, formalization and applications. Descriptions of the Chord and Synapse protocols using the ASM formalism is presented, and both a high-level and a re_ned proof of the correctness of the Chord formalization is given. A probabilistic assessment of the exhaustiveness of the Synapse protocol is performed. An updated version of the Proposal of metadata schemata for movable cultural heritage as well as a Proposal of metadata schemata for describing collections are provided. Based of the Chord protocol, a Distributed catalog of digitized collections of Serbian cultural herigate is implemented.Doktorska disertacija se bavi temama vezanim za prekrivajuće mreže, njihovom definicijom, formalizacijom i primenama. Dati su opisi Chord i Synapse protokola korišćenjem ASM formalizma, kao i dokaz korektnosti formalizacije Chord protokola na visokom nivou, kao i njegovo profinjenje. Izvršena je verovatnosna ocena uspešnosti pretrage pomoću Synapse protokola. Predstavljena je ažurirana verzija Predloga sheme meta podataka za pokretna kulturna dobra, kao i Predlog sheme meta podataka za opis kolekcija. Implementiran je Distribuirani katalog digitalizovanih kolekcija kulturne baštine Srbije zasnovan na Chord protokolu

Rational Design of Photochromic Analogues of Tricyclic Drugs

Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically, they cause serious adverse effects that limit their use. To obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo-analogues of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo. Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M1 vs M2 subtype selectivity. These photoswitchable “crypto-azologs” of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects

Structure and interaction studies of beta-amyloid in the search for new lead compounds for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that effects the aging population worldwide. In this study three hypotheses of AD are explored, the β-amyloid cascade hypothesis, the β-amyloid metal binding hypothesis and the oxidative stress hypothesis are explored. In the first case compounds from the South African Natural Compounds Database (SANCDB) are docked to models of β-amyloid fibrils and the properties of these fibrils under pulling simulations are compared to a known small molecule disruptor of β-amyloid, wgx-50. In these simulations SANCDB compounds are identified that disrupt β-amyloid in a similar manner to wgx-50. In these simulations the disruption to the free energy of binding of chains to the fibrils is quantified. For metal binding and oxidative stress hypotheses, problems in simulation arise due to only fragments of β-amyloid being present in the Research Collaboratory for Structural Bioinformatics protein data bank (RCSB PDB), as determined from NMR experiments. In this work, β-amyloid is set up under periodic boundary conditions to simulate a fibril under reasonable computational time. Within these periodic boundary conditions, β-amyloid has been solvated in copper and zinc rich environments and diffusion of these metals around the fibrils has been explored. The localization of these metals (in simulation only using van der Waal’s and electrostatic terms) around the fibril has led us to explore other possible metal binding sites. Metal bound to the infinite fibril has been optimized at the QM/MM level and some of the reactive oxygen species in the presence of the fibril are quantified

Identification of small molecules with reactivities against multiple pathogenic elements of alzheimer???s disease

Department of ChemistryAlzheimer???s disease (AD) remains a formidable threat against mankind since its introduction in 1906. As a progressive neurodegenerative disease responsible for the majority of dementia cases, AD remains cureless. Along with the lack of an effective cure, the aging world population depicts an imminent epidemic and pessimistic outlook regarding the disease. Research endeavors dedicated to understanding the etiopathology of AD and developing therapeutics have led to significant progress in our comprehension of AD. However, attempts of formulating treatments with the ability to stop AD progression have proven futile. More specifically, various pathological factors have been identified and implicated as sources of neurodegeneration leading to AD. These include amyloid-??? (A???), metal ions, acetylcholinesterase (AChE), and reactive oxygen species (ROS) indicated in the various hypotheses attempting to elucidate the main cause of AD: amyloid cascade, metal ion, cholinergic, and oxidative stress, respectively. Therapeutic approaches targeting these individual pathogenic features have yet to result in clinically effective treatment strategies. Such failures have led to a shift in paradigm to understand the interconnections between these pathological factors to account for AD???s complexity. Intricacies of the pathogenic elements of AD present experimental challenges in investigating their inter-relationships. Multifunctional molecules capable of targeting multiple pathogenic factors of AD could, therefore, be beneficial in our attempt to understand AD. In this thesis, we first aim to identify molecular frameworks conferring multifunctionality against multiple pathogenic factors of AD [i.e., A???, metal-bound A??? (metal???A???), AChE, and ROS] from the structures of both natural products and synthetic molecules. Such chemical entities will be helpful in furthering our understanding of the relationships among the different pathological factors and assist the development of physiologically viable chemical tools with suitable bioapplicability. We hope that these findings contribute towards an improved capacity for experimentally examining the complex network of AD pathology and a closer understanding of its inner workings. In Chapter 1, we briefly introduce the multifaceted pathology of AD and discuss the various pathogenic elements implicated in driving the development and progression of the disease. In Chapter 2, a naturally occurring isoflavone, orobol, is presented as a multifunctional molecule with modulative reactivity against four specific pathogical factors of AD: metal-free A???, metal???A???, ROS, and AChE. In chapter 3, the molecular structures of 12 flavonoids, selected based on three multifunctional flavonoids (i.e., quercetin, luteolin, and orobol) were examined with respect to their reactivities against metalfree A???, metal???A???, ROS, and AChE. This study aimed to identify the molecular features responsible for instilling these flavonoids with the ability to modulate the aforementioned targets. Four major structural attributes were identified to contribute to such versatility of select flavonoids. In chapter 4, pre-approved anti-depressant molecules were explored as candidates of drug repurposing to discover new multifunctional molecules against AD and increase our database of structural moieties associated with multifunctionality. The versatile reactivity of three synthetic compounds were demonstrated against Cu(II)???A???, free radicals, and AChE. Overall, we present a number of multifunctional chemicals capable of targeting several major pathogenic elements of AD. We believe that these molecules will contribute significantly towards our efforts to better comprehend the multifaceted etiopathology of AD by serving as chemical tools that allow us to directly perform experiments regarding the pathogenic connections between metal-free A???, metal???A???, ROS, and AChE at in vitro and possibly clinical stages. Moreover, identification of the structural features instilling multifunctionality could facilitate the design and development of biocompatible therapeutics capable of simultaneously targeting multiple pathologies of AD and their connections. Our approaches will provide the foundation for developing effective and efficient methods of elucidating fundamental connections among the pathological factors of AD at the molecular level and identifying efficacious therapeutics against AD capable of controlling the progression of neurodegeneration.clos