894 research outputs found
2015 Conference Abstracts: Annual Undergraduate Research Conference at the Interface of Biology and Mathematics
Schedule and abstract book for the Seventh Annual Undergraduate Research Conference at the Interface of Biology and Mathematics
Date: November 21-22, 2015Plenary speaker: Robert Smith, University of OttawaFeatured speaker: Rachel Lenhart, University of Wisconsin, Madiso
Geographic Information System; Route Tracking System Using Personal Digital Assistant (PDA)
Nowadays the mobile mapping which incorporation with handheld PDA devices
for field data collection is rapidly expanding it wings of Geographic Information
System (GIS). While the wireless technology is increasing through time, the usage
of mobile GIS has become a very useful tool in any organizations and companies.
The introduction of mobile technology actually has resulted in the fundamental
paradigm which shifts into the integration of a centralized GIS database engine
and other web presentation formats with the mobile data collection units. For
mobile mapping, the lightweight GIS application ArcPad and small portable
computers such as for example; the Compaq PocketPC are a viable option for field
GIS. ESRI® ArcPad™ software is a mobile mapping and geographic information
system (GIS) technology. Mobile computing is creating fundamental changes in the
way we utilize geography with the ability to bring your work with you and interact
directly with the world around you. Mobile GIS comprises the integration of four
technologies: GIS, lightweight hardware, the global positioning system (GPS), and
wireless communication. Here it emphasis the research on the GIS, more on
focusing on the GIS in the mobile environment. It presents the idea of applying
GIS concept in tracking route where mobile GIS will combine up with GPS as a
tracking movement coordinate tool. The Sashimi Model is used as a guidance to
monitor the project progress. The methodology is suitable as it stresses on both
side which is the requirement side and the implementation side. A simulation of
route tracking system would be presented as the findings of the while research.
Further more the simulation present the idea of the real-time tracking the route
using data output from the GPS receiver
Fluorescence Spectroscopy of Recoverin Function and Conformation
Recoverin is a neuronal calcium sensor protein (NCS protein) from the vertebrate photoreceptor which is involved in light adaptation. Recoverin changes its conformation upon sequential binding of two calcium ions. This conformational change induces the extrusion of a covalently attached myristoyl residue from a hydrophobic binding pocket which enables Recoverin to interact with lipid membranes (calcium myristoyl switch). In this thesis, I report on my investigation of Recoverin�s calcium myristoyl switch, using a recently developed modification of fluorescence correlation spectroscopy (FCS) that is called dual focus FCS (2fFCS). This method allows for measuring absolute diffusion coefficients with an accuracy of better than a few percent. Recoverin, and the Recoverin mutants E85Q and E121Q which bind only one or no Ca2+, respectively, were labeled with the fluorescent dye Alexa647. Differences in the hydrodynamic radius due to conformational changes of Recoverin and its mutants upon calcium binding were monitored by measuring the diffusion coefficient of these molecules as a function of free calcium concentration. The calcium dependent interaction of Recoverin with lipid membranes was measured in solutions of small unilamellar vesicles (SUVs) of different lipid composition. Again, diffusion measurements were used to determine the fraction of free and lipid bound Recoverin using the strongly different diffusion coefficients of both fractions. To account for the fluorescence brightness difference of the dye label when in solution and close to a lipid membrane, a new three photon correlation analysis was developed and tested
Molecular dynamics and virtual screening approaches in drug discovery
Computer-aided drug discovery (CADD) methods are now routinely used in the
preclinical phase of drug development. Powerful high-performance computing
facilities and the extremely fast CADD methods constantly scale up the coverage of
drug-like chemical space achievable in rational drug development. In this thesis,
CADD approaches were applied to address several early-phase drug discovery
problems. Namely, small molecule binding site detection on a novel target protein,
virtual screening (VS) of molecular databases, and characterization of small
molecule interactions with metabolic enzymes were studied. Various CADD
methods, including molecular dynamics (MD) simulations in mixed solvents,
molecular docking, and binding free energy calculations, were employed. Co-solvent
MD simulations detected biologically relevant binding sites and provided guidance
for screening potential protein-protein interaction inhibitors for a crucial protein of
the SARS-CoV-2. VS with fragment- and negative image-based (F-NIB) models
identified three active and structurally novel inhibitors of the putative drug target
phosphodiesterase 10A. MD simulations and docking provided detailed insights on
the effects of active site structural flexibility and variation on the binding and
resultant metabolism of small molecules with the cytochrome P450 enzymes. The
results presented in this thesis contribute to the increasing evidence that supports
employment and further development of CADD approaches in drug discovery.
Ultimately, rational drug development coupled with CADD may enable higher
quality drug candidates to the human studies in the future, reducing the risk of
financially and temporally costly clinical failure.
KEYWORDS: Structure-based drug development, Computer-aided drug discovery
(CADD), Molecular dynamics (MD) simulation, Virtual screening (VS), Fragmentand
negative image-based (F-NIB) model, Structure-activity relationship (QSAR),
Cytochrome P450 ligand binding predictionMolekyylidynamiikka- ja virtuaaliseulontamenetelmät lääkeaine-etsinnässä
Tietokoneavusteista lääkeaine-etsintää käytetään nykyisin yleisesti prekliinisessä lääketutkimuksessa. Suurteholaskenta ja äärimmäisen nopeat tietokoneavusteiset lääkeaine-etsintämenetelmät mahdollistavat jatkuvasti kattavamman lääkkeenkaltaisten molekyylien kemiallisen avaruuden seulonnan. Tässä väitöskirjassa tietokonepohjaisia menetelmiä hyödynnettiin lääketutkimuksen prekliiniseen vaiheeseen liittyvissä tyypillisissä tutkimusongelmissa. Työhön kuului pienmolekyylien sitoutumisalueiden tunnistus uuden kohdeproteiinin rakenteesta, molekyylitietokantojen virtuaaliseulonta sekä pienmolekyylien ja metabolian entsyymien välisten vuorovaikutusten tietokonemallinnus. Työssä käytettiin useita tietokoneavusteisen lääkeaine-etsinnän menetelmiä, sisältäen molekyylidynamiikkasimulaatiot (MD-simulaatiot) vaihtuvissa liuottimissa, molekulaarisen telakoinnin ja sitoutumisenergian laskennan. Orgaanisen liuottimen ja veden sekoituksessa tehdyt MD-simulaatiot tunnistivat biologisesti merkittäviä sitoutumisalueita SARS-CoV-2:n tärkeästä proteiinista ja ohjasivat infektioon liittyvän proteiini-proteiinivuorovaikutuksen potentiaalisten estäjien etsintää. Virtuaaliseulonnalla tunnistettiin kolme rakenteellisesti uudenlaista tunnetun lääkekehityskohteen, fosfodiesteraasi 10A:n, estäjää hyödyntäen fragmentti- ja negatiivikuvamalleja. MD-simulaatiot ja telakointi tuottivat yksityiskohtaista tietoa sytokromi P450 entsyymien aktiivisen kohdan rakenteen jouston ja muutosten vaikutuksesta pienmolekyylien sitoutumiseen ja metaboliaan. Tämän väitöskirjan tulokset tukevat kasvavaa todistusaineistoa tietokoneavusteisen lääkeaine-etsinnän käytön ja kehityksen hyödyllisyydestä prekliinisessä lääketutkimuksessa. Tietokoneavusteinen lääkeaine-etsintä voi lopulta mahdollistaa korkeampilaatuisten lääkekandidaattien päätymisen ihmiskokeisiin, pienentäen taloudellisesti ja ajallisesti kalliin kliinisen tutkimuksen epäonnistumisen riskiä.
AVAINSANAT: Rakennepohjainen lääkeainekehitys, Tietokoneavusteinen lääkeaine-etsintä, Molekyylidynamiikkasimulaatio (MD-simulaatio), Virtuaaliseulonta, Fragmentti- ja negatiivikuvamalli, Rakenne-aktiivisuussuhde, Sytokromi P450 ligandien sitoutumisen ennustu
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