Advances in Drug Discovery – Chemistry and Biology

19.00

8.30–8.40

8.40–9.20

9.20–10.20

Base-modified nucleosides and nucleotides as new cytostatics and building blocks for enzymatic synthesis of modified nucleic acids (Michal Hocek)

In the Hocek group (Joint laboratory of IOCB and Charles University in bioorganic and medicinal chemistry of nucleic acids), novel types of modified derivatives and analogues of nucleobases, nucleosides, nucleotides and nucleic acids are designed and prepared for applications in all areas of biomedicinal sciences (medicinal chemistry, biochemistry, chemical biology, bioanalysis etc.). Basic developments of methodology for the synthesis of these modified biomolecules are performed largely using modern methods (including metal- or enzyme-catalyzed reactions). Biological activity (cytostatic, antiviral etc.) of the novel nucleobases, nucleosides and nucleotides is systematically studied in collaboration with several groups both in academia and in pharmaceutical industry. Several collaborative projects also address chemical biology of nucleic acids (i.e. DNA polymerase specificity and fidelity). Functionalized nucleic acids bearing diverse interesting and useful substituents are another goal of our group. For details, see: http://www.uochb.cas.cz/hocekgroup

10.20–10.40

10.30–11.10

The sugar code (Jitka Moravcová)

Research in the field of chemistry and stereochemistry of saccharides and bioactive natural products.

11.10–11.50

Antimalarials (Zlatko Janeba)

Research interest of the group is mainly targeted at design and synthesis of biologically active antimetabolites that are able to interact with various enzymes of nucleos(t)ide metabolism. A special attention has been devoted to potential inhibitors of important viral and plasmodial enzymes and to inhibitors of bacterial adenylate cyclases. http://www.uochb.cz/web/structure/901.html

11.50–13.20

13.20–14.00

Antivirals (Marcela Krečmerová)

Research in the field of medicinal chemistry targeted to chemically modified nucleoside and nucleotide analogues as antivirals and cytostatic agents. A special attention is paid to 5-azacytosine related compounds for epigenetic therapy of cancer and new ways to improvement of pharmacological profile of active structures (prodrug design). For details see: http://www.uochb.cz/web/structure/899.html?lang=en

14.00–14.40

Antibiotics (Rejman)

Our research is devoted to the synthesis and evaluation of biological properties of modified nucleosides, nucleotides, and oligonucleotides. Specifically, in Rejman's lab, we are focused in the search for new approaches in the treatment of microbial infections. Currently, the main subject includes design and synthesis of novel antibacterial and antiplasmodial compounds.

14.40–15.00

15.00–16.00

Dignostics and Pharmacs Used in Asthma (Petr Kačer)

Approaches to diagnostics and pharmacotherapy of pulmonary diseases with emphasis on bronchial asthma will be presented. The basic pharmacology of methylxanthines, cromolyn, leucotriene pathway inhibitors, and monoclonal anti-IgE antibody agents, whose medical use is almost exclusively for pulmonary diseases, will be discussed.

16.00–16.45

Asymmetric hydrogenation in drug synthesis (Jiří Vaclavik)

Catalytic asymmetric hydrogenation of the C=O and C=N functional groups is a convenient method of direct synthesis of enantioenriched alcohols and amines. The first part will be devoted to the mechanistic principles of enantioselective hydrogenation. The second part will show selected examples of successful application of the reaction in drug synthesis.

8.30–9.30

HIV – threat and hope of humankind (Tomáš Ruml)

Our effort is to reveal mechanism of transport of structural proteins that form retroviral (e.g. HIV) virus-like particles. Subcellular localization of viral proteins/particles and mechanisms of their intracellular transport is monitored by microscopy using fluorescently labeled proteins in living cells in real time. The aim of this study is to contribute to development of new antivirotics and vectors with their potential use in gene therapy (specific targeting of therapeutic molecules to their effective places, for example to tumors). This study is closely connected with preparation of fluorescent molecules for tumor imaging and diagnostics.

9.30–10.20

Insulin and diabetes research (Jiří Jiráček)

Our research group in IOCB is engaged in structure-activity studies of insulin and insulin-like growth factors 1 and 2 (IGFs). These important hormones share similar 3-D structures and cell membrane receptors. Our general goal in insulin/IGF research is understanding of the structural basis for the different cellular responses, metabolic and mitogenic, generated by insulin and IGFs, respectively. We develop analogues of insulin and IGFs to study their interactions with cognate receptors. (http://www.uochb.cz/web/structure/184.html)

10.20–10.30

10.30–11.20

Metabolic Syndrome (Lenka Maletinská)

Main research interests focus on peptides involved in food intake regulation and mechanisms of their action Recently involved in development of novel stable neuropeptide analogs as a potential anti-obesity agents The research of our group in IOCB is focused on development and mechanism of action of stabilized analogs of food intake regulating neuropeptides (prolactin-releasing peptide, CART peptide) and ghrelin for potential treatment of food intake disorders such as obesity or cachexia. We study the above mentioned peptides both in vitro in physiologically relevant cell lines expressing respective peptide receptors and in vivo in mouse and rat models of obesity and leptin and insulin resistance, as well as cachexia.

11.20–12.20

Theranostics: Chemical Tools for Diagnostics and targeted Delivery of Drugs (Jan Konvalinka)

Laboratory of Jan Konvalinka at the IOCB and Faculty of Natural Sciences of the Charles University in Prague works on identification, characterisation and exploitation of enzymes (mostly proteases) as therapeutic targets. The research is focused mainly on the aspartic protease from HIV (structure-function characterization, inhibitor design and testing, development of antiviral resistance), serine racemase from mammalian nervous systém (recombinant expression and inhibitor design) and glutamate carboxypeptidase II (characterisation of the enzyme as a neuropeptidase and prostate specific membrane antigen).

12.20–13.40

13.40–14.30

New Building for Organic synthesis at the IOCB/ICTP facility – tour

14.30–21.00

Guided Tour + Beer Dinner

9.00–10.00

X-ray crystallography and structure-based drug design (Pavlína Řezáčová)

The main interest of the research team of Structural biology at IOCB is in the structural studies of proteins having biological or medicinal interest. We use structural knowledge to understand and modulate the biological roles and functions of proteins. In our structure-based drug discovery project, targeting enzymes from pathogenic organisms (e.g. HIV protease, Candida proteases) as well as human enzymes (e.g. carbonic anhydrases), the knowledge of protein structures provides a platform for the rational design of specific inhibitors. (http://www.uochb.cz/web/rezacova)

10.00–11.00

In Sillico Drug Design (Pavel Hobza)

Computational, theoretical and quantum chemistry. Main projects : noncovalent interactins and their role in biodisciplines, In Silico Drug Design. Recently the new scoring function based on quantum mechanical Hamiltonian have been introduced in our laboratory. The total score approximating change of the free energy of the formation of protein - ligand complex is constructed as the sum gas-phase interaction energy, desolvation energy of protein and ligand, deformation energy of protein and ligand and entropy change accompanying formation of the complex.First studies on HIV protease, CDK2 and CK2 kinases have shown that theoretical score correlates well with biological activity of different inhibitors and the method could be thus used in In Silico Drug Design.

11.00–11.10

11.10–12.00

Exploring chemical space for drug discovery (Dan Svozil)

Chemical space is populated by all possible (i.e., chemically meaningful and stable) organic compounds. It represents an important concept in contemporary chemoinformatics research, and its exploration may lead to the discovery of novel drugs or tools for chemical biology. In this lecture, various computational tools and techniques for representing and navigating chemical space will be introduced and discussed.

Main scientific interests of our research group are computational chemical biology, computational chemogenomics and analysis of high-throughput screening data. In cooperation with the Institute of Molecular Genetics of the ASCR, we develop novel ligands for human nuclear receptors using wide range of chemoinformatics techniques including virtual screening, quantitative structure-activity relationship modeling or chemical space exploration.

12.00–12.50

LC-SPE-NMR/MS, the modern tool for natural product and pharmaceutical research (Marek Kuzma)

LC-SPE-NMR/MS, the hyphenated technique comprising NMR spectrometry with HPLC, solid phase extraction (SPE) and mass spectrometry, represents one the advanced methods for the fast and reliable molecular structure elucidation in the organic chemistry. It brings together separation power of the liquid chromatography and NMR capabilities for structure elucidation.

12.50–14.00

14.00–15.00

Utilization of metabolic transformations in drug development; prodrugs, soft drugs, and more (Stanislav Rádl)

Results of metabolic and pharmacokinetic studies are integral parts of the early drug development. In case of metabolic inactivation, the site of the metabolic change could be protected by suitable substitution. On the other hand, metabolic reaction leading to active metabolites can substantially prolong the activity. Modification of a drug providing an inactive compound that is metabolically activated in the body is the basis of the prodrug approach. On the opposite, the soft drug concept is based on fast metabolic inactivation of a drug after exerting its desired therapeutic effect.

All the mentioned approaches will be both theoretically explained and illustrated on relevant case studies.

The lecturer’s fields of special interest include heterocyclic chemistry and medicinal chemistry, especially antibacterial chemotherapy and therapy of hypertension, as well as history of medicinal chemistry.

15.00–16.00

New synthetic drugs: from cul de sacs of pharmaceutical research to the illicit street drugs (Igor Linhart)

Main research interest of the author lies in chemical toxicology, particularly metabolism of xenobiotics, interactions of reactive metabolites with proteins and DNA and their toxicological consequences. This lecture, however, will describe the phenomenon of "designer drugs," i.e., illicit street drugs often designed by simple modifications of known active substances including those, which did not pass successfully clinical trials. Recent history of their proliferation and possibilities of their identification and quantification in body fluids will be dicussed.

16.00–16.45

Biologicals - present status (Martin Fusek)

Main interest in the field of interaction of chemistry and biology.

16.45

Official end of the Summer school