The application of pharmacoinformatics in enhancing pharmaceutical care of patients with cancer

Ph.DDOCTOR OF PHILOSOPH

Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery

GPCR modeling approaches are widely used in the hit-to-lead (H2L) and lead optimization (LO) stages of drug discovery. The aims of these modeling approaches are to predict the 3D structures of the receptor-ligand complexes, to explore the key interactions between the receptor and the ligand and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this book chapter, we present a brief survey of key computational approaches integrated with hierarchical GPCR modeling protocol (HGMP) used in hit-to-lead (H2L) and in lead optimization (LO) stages of structure-based drug discovery (SBDD). We outline the differences in modeling strategies used in H2L and LO of SBDD and illustrate how these tools have been applied in three drug discovery projects

Development and application of distributed computing tools for virtual screening of large compound libraries

Im derzeitigen Drug Discovery Prozess ist die Identifikation eines neuen Targetproteins und dessen potenziellen Liganden langwierig, teuer und zeitintensiv. Die Verwendung von in silico Methoden gewinnt hier zunehmend an Bedeutung und hat sich als wertvolle Strategie zur Erkennung komplexer Zusammenhänge sowohl im Bereich der Struktur von Proteinen wie auch bei Bioaktivitäten erwiesen. Die zunehmende Nachfrage nach Rechenleistung im wissenschaftlichen Bereich sowie eine detaillierte Analyse der generierten Datenmengen benötigen innovative Strategien für die effiziente Verwendung von verteilten Computerressourcen, wie z.B. Computergrids. Diese Grids ergänzen bestehende Technologien um einen neuen Aspekt, indem sie heterogene Ressourcen zur Verfügung stellen und koordinieren. Diese Ressourcen beinhalten verschiedene Organisationen, Personen, Datenverarbeitung, Speicherungs- und Netzwerkeinrichtungen, sowie Daten, Wissen, Software und Arbeitsabläufe. Das Ziel dieser Arbeit war die Entwicklung einer universitätsweit anwendbaren Grid-Infrastruktur - UVieCo (University of Vienna Condor pool) -, welche für die Implementierung von akademisch frei verfügbaren struktur- und ligandenbasierten Drug Discovery Anwendungen verwendet werden kann. Firewall- und Sicherheitsprobleme wurden mittels eines virtuellen privaten Netzwerkes gelöst, wohingegen die Virtualisierung der Computerhardware über das CoLinux Konzept ermöglicht wurde. Dieses ermöglicht, dass unter Linux auszuführende Aufträge auf Windows Maschinen laufen können. Die Effektivität des Grids wurde durch Leistungsmessungen anhand sequenzieller und paralleler Aufgaben ermittelt. Als Anwendungsbeispiel wurde die Assoziation der Expression bzw. der Sensitivitätsprofile von ABC-Transportern mit den Aktivitätsprofilen von Antikrebswirkstoffen durch Data-Mining des NCI (National Cancer Institute) Datensatzes analysiert. Die dabei generierten Datensätze wurden für liganden-basierte Computermethoden wie Shape-Similarity und Klassifikationsalgorithmen mit dem Ziel verwendet, P-glycoprotein (P-gp) Substrate zu identifizieren und sie von Nichtsubstraten zu trennen. Beim Erstellen vorhersagekräftiger Klassifikationsmodelle konnte das Problem der extrem unausgeglichenen Klassenverteilung durch Verwendung der „Cost-Sensitive Bagging“ Methode gelöst werden. Applicability Domain Studien ergaben, dass unser Modell nicht nur die NCI Substanzen gut vorhersagen kann, sondern auch für wirkstoffähnliche Moleküle verwendet werden kann. Die entwickelten Modelle waren relativ einfach, aber doch präzise genug um für virtuelles Screening einer großen chemischen Bibliothek verwendet werden zu können. Dadurch könnten P-gp Substrate schon frühzeitig erkannt werden, was möglicherweise nützlich sein kann zur Entfernung von Substanzen mit schlechten ADMET-Eigenschaften bereits in einer frühen Phase der Arzneistoffentwicklung. Zusätzlich wurden Shape-Similarity und Self-organizing Map Techniken verwendet um neue Substanzen in einer hauseigenen sowie einer großen kommerziellen Datenbank zu identifizieren, die ähnlich zu selektiven Serotonin-Reuptake-Inhibitoren (SSRI) sind und Apoptose induzieren können. Die erhaltenen Treffer besitzen neue chemische Grundkörper und können als Startpunkte für Leitstruktur-Optimierung in Betracht gezogen werden. Die in dieser Arbeit beschriebenen Studien werden nützlich sein um eine verteilte Computerumgebung zu kreieren die vorhandene Ressourcen in einer Organisation nutzt, und die für verschiedene Anwendungen geeignet ist, wie etwa die effiziente Handhabung der Klassifizierung von unausgeglichenen Datensätzen, oder mehrstufiges virtuelles Screening.In the current drug discovery process, the identification of new target proteins and potential ligands is very tedious, expensive and time-consuming. Thus, use of in silico techniques is of utmost importance and proved to be a valuable strategy in detecting complex structural and bioactivity relationships. Increased demands of computational power for tremendous calculations in scientific fields and timely analysis of generated piles of data require innovative strategies for efficient utilization of distributed computing resources in the form of computational grids. Such grids add a new aspect to the emerging information technology paradigm by providing and coordinating the heterogeneous resources such as various organizations, people, computing, storage and networking facilities as well as data, knowledge, software and workflows. The aim of this study was to develop a university-wide applicable grid infrastructure, UVieCo (University of Vienna Condor pool) which can be used for implementation of standard structure- and ligand-based drug discovery applications using freely available academic software. Firewall and security issues were resolved with a virtual private network setup whereas virtualization of computer hardware was done using the CoLinux concept in a way to run Linux-executable jobs inside Windows machines. The effectiveness of the grid was assessed by performance measurement experiments using sequential and parallel tasks. Subsequently, the association of expression/sensitivity profiles of ABC transporters with activity profiles of anticancer compounds was analyzed by mining the data from NCI (National Cancer Institute). The datasets generated in this analysis were utilized with ligand-based computational methods such as shape similarity and classification algorithms to identify and separate P-gp substrates from non-substrates. While developing predictive classification models, the problem of imbalanced class distribution was proficiently addressed using the cost-sensitive bagging approach. Applicability domain experiment revealed that our model not only predicts NCI compounds well, but it can also be applied to drug-like molecules. The developed models were relatively simple but precise enough to be applicable for virtual screening of large chemical libraries for the early identification of P-gp substrates which can potentially be useful to remove compounds of poor ADMET properties in an early phase of drug discovery. Additionally, shape-similarity and self-organizing maps techniques were used to screen in-house as well as a large vendor database for identification of novel selective serotonin reuptake inhibitor (SSRI) like compounds to induce apoptosis. The retrieved hits possess novel chemical scaffolds and can be considered as a starting point for lead optimization studies. The work described in this thesis will be useful to create distributed computing environment using available resources within an organization and can be applied to various applications such as efficient handling of imbalanced data classification problems or multistep virtual screening approach

Pharmacies and medication information system in Jeddah City, Saudi Arabia

It is acknowledged that the introduction of Health Information Systems (HIS) have contributed to the reorganization of the methods used in health services for Health Information Management. Managers in the health services benefit from Health Information Systems provision both strategically and operationally, for example in the planning of new services and more routinely in assisting health professionals in making informed medical decisions. Health services in developed countries already have Health Information Systems (HIS) in place but their adoption in developing countries has been less widespread. In Jeddah, KSA there is a lack of a unified HIS. Health service provision in Jeddah is spread between a wide range of governmental and private health services. The lack of unification of these services and a bespoke HIS has led to problems for both patients and healthcare professionals. This research focuses on the methods of prescribing medication, provision of supplies and the dispensing of medication within pharmacies. [Continues.

Information Technology Development Needs in Community Pharmacies : A Strategic Approach

In the context of health care, information technology (IT) has an important role in the operational infrastructure, ranging from business management to patient care. An essential part of the system is medication management in inpatient and outpatient care. Community pharmacists strategy has been to extend practice responsibilities beyond dispensing towards patient care services. Few studies have evaluated the strategic development of IT systems to support this vision. The objectives of this study were to assess and compare independent Finnish community pharmacy owners and staff pharmacists priorities concerning the content and structure of the next generation of community pharmacy IT systems, to explore international experts visions and strategic views on IT development needs in relation to services provided in community pharmacies, to identify IT innovations facilitating patient care services and to evaluate their development and implementation processes, and to assess community pharmacists readiness to adopt innovations. This study applied both qualitative and quantitative methods. A qualitative personal interview of 14 experts in community pharmacy services and related IT from eight countries and a national survey of Finnish community pharmacy owners (mail survey, response rate 53%, n=308), and of a representative sample of staff pharmacists (online survey, response rate 22%, n=373) were conducted. Finnish independent community pharmacy owners gave priority to logistical functions but also to those related to medication information and patient care. The managers and staff pharmacists have different views of the importance of IT features, reflecting their different professional duties in the community pharmacy. This indicates the need for involving different occupation groups in planning the new IT systems for community pharmacies. A majority of the international experts shared the vision of community pharmacy adopting a patient care orientation; supported by IT-based documentation, new technological solutions, access to information, and shared patient data. Community pharmacy IT innovations were rare, which is paradoxical because owners and staff pharmacists perception of their innovativeness was seen as being high. Community pharmacy IT systems development processes usually had not undergone systematic needs assessment research beforehand or evaluation after the implementation and were most often coordinated by national governments without subsequent commercialization. Specifically, community pharmacy IT developments lack research, organization, leadership and user involvement in the process. Those responsible for IT development in the community pharmacy sector should create long-term IT development strategies that are in line with community pharmacy service development strategies. This could provide systematic guidance for future projects to ensure that potential innovations are based on a sufficient understanding of pharmacy practice problems that they are intended to solve, and to encourage strong leadership in research, development of innovations so that community pharmacists potential innovativeness is used, and that professional needs and strategic priorities will be considered even if the development process is led by those outside the profession.Strateginen näkökulma apteekkien tietojärjestelmien kehittämiseen Suomalaisten apteekkien strategiana on ollut laajentaa vastuuta lääkkeiden toimittamisesta potilaiden lääkehoitoa tukeviin palveluihin. Tietotekniikan avulla toteutettu lääkehoidon hallinta vahvistaa apteekkien roolia merkittävänä lääkehuollon toimijana. Tietotekniikan osuutta apteekkien strategian toteuttamisessa on tähän mennessä tutkittu vähän. Suomalaiset apteekkarit kokivat logistiikkaa tukevat tietojärjestelmän ominaisuudet erittäin tärkeiksi, mutta arvostivat myös lääkityksen hallintaan liittyviä ominaisuuksia. Apteekissa työskentelevien eri ammattiryhmien näkemykset tietojärjestelmän eri ominaisuuksien tärkeydestä poikkesivat toisistaan, omien työtehtävien kannalta tutut ominaisuudet koettiin tärkeiksi. Tutkimustulokset osoittavat, ettei tietojärjestelmiä voida kehittää ainoastaan apteekkareiden näkemysten perusteella, vaan arvokasta tietoa saadaan myös muulta henkilöstöltä ja erityisesti asiakaspalvelussa työskenteleviltä farmaseuteilta, joilla on keskeinen merkitys asiakaslähtöisissä toiminnoissa. Kansainvälisistä asiantuntijoista suurin osa jakaa vision apteekkien potilaskeskeisestä toimintamallista, jota tietotekniset sovellukset tukevat. Tutkimuksen mukaan apteekkien tietotekniset innovaatiot ovat harvinaisia, vaikka apteekkilaiset itse arvioivat oman innovatiivisuutensa korkeaksi. Kansainvälisesti apteekkien tietojärjestelmien kehitysprosessit eivät noudattaneet teoreettisen viitekehyksen mallia, vaan tyypillisimmin tutkimusvaihe ennen kehitystyötä sekä toteutusvaiheen jälkeen jäi puuttumaan. Lisäksi kehitysprosessi oli yleensä koordinoitu yhteiskunnan taholta ilman varsinaista kaupallista tuotteistusta. Erityisen puutteellisina osa-alueina kansainväliset asiantuntijat pitivät tutkimusta, organisointia, johtamista sekä tulevien käyttäjien osallistumista kehitystyöhön. Apteekkien tietojärjestelmien kehittämisestä vastaavien tahojen tulisi luoda pitkän aikavälin strategia tukemaan ammattiapteekkistrategiaa ja ohjaamaan tulevia projekteja, jotta varmistettaisiin innovaatioiden kehittäminen apteekkityön tarpeisiin. Lisäksi tarvitaan vahvaa johtajuutta tutkimuksessa ja kehitystyössä, jotta apteekeissa työskentelevien ammattilaisten innovatiivisuus tulee hyödynnettyä. Apteekkien ammatilliset tarpeet ja strategia tulee huomioida apteekin tietojärjestelmien kehitystyössä. Tutkimuksen aineisto kerättiin suomalaisille apteekkareille, proviisoreille ja farmaseuteille osoitetulla kyselytutkimuksella sekä kansainvälisten asiantuntijoiden haastattelututkimuksella

Empowering pharmacoinformatics by linked life science data

With the public availability of large data sources such as ChEMBLdb and the Open PHACTS Discovery Platform, retrieval of data sets for certain protein targets of interest with consistent assay conditions is no longer a time consuming process. Especially the use of workflow engines such as KNIME or Pipeline Pilot allows complex queries and enables to simultaneously search for several targets. Data can then directly be used as input to various ligand- and structure-based studies. In this contribution, using in-house projects on P-gp inhibition, transporter selectivity, and TRPV1 modulation we outline how the incorporation of linked life science data in the daily execution of projects allowed to expand our approaches from conventional Hansch analysis to complex, integrated multilayer models