Predictive methods as a powerful tool in drug discovery

A development of a new drug is an extremely complex process, with average costs over $900 million and a time span up to 15 years. Regulatory hurdles are progressively higher, costs are escalating and the competition is ever tougher. All these factors drive pharmaceutical companies to shorten the Research & Development (R&D) process as much as possible. Consequently, methodologies for increasing productivity of the R&D processes become more and more important. One of them, a linear drug discovery paradigm starts from numerous genes and ends with prospective drugs. It consists of four inter-related building blocks that together provide a whole new platform that drives a focus on R&D efforts and commercial capabilities, on use of product and capability partnerships, on provision of customer solutions (prevention, prediction and follow-up, not just treatment), and finally on preference of organizations based on a business unit model instead of a functional one. Companies are to find a combination of these building blocks that best fits their strengths, improves returns and minimizes involved risks. Predictive methodology, together with other prediction approaches applied in drug discovery, is powerful tool that is quickly becoming more and more important, if not essential, in modern drug development. In this review, a brief description of new trends, as well as new challenges of today\u27s drug discovery is presented from the insider perspective

Macromolecular Databases – A Background of Bioinformatics

We propose a novel quasi‐Bayesian Metropolis‐within‐Gibbs algorithm that can be used to estimate drifts in the shock volatilities of a linearized dynamic stochastic general equilibrium (DSGE) model. The resulting volatility estimates differ from the existing approaches in two ways. First, the time variation enters non‐parametrically, so that our approach ensures consistent estimation in a wide class of processes, thereby eliminating the need to specify the volatility law of motion and alleviating the risk of invalid inference due to mis‐specification. Second, the conditional quasi‐posterior of the drifting volatilities is available in closed form, which makes inference straightforward and simplifies existing algorithms. We apply our estimation procedure to a standard DSGE model and find that the estimated volatility paths are smoother compared to alternative stochastic volatility estimates. Moreover, we demonstrate that our procedure can deliver statistically significant improvements to the density forecasts of the DSGE model compared to alternative methods.PostprintPeer reviewe

Kombinirani in silico i in vitro pristup pronalaženju spojeva s mogućim ljekovitim djelovanjem

The purpose of High Throughput Screening (HTS) in pharmaceutical industry is to identify, as soon as possible, compounds that are good starting points for successful new drug development process. Experts from this area study the chemical structures of so called »hit« compounds that have been found to interact with the target protein, interfere with proliferation of different types of cells or stop bacterial or fungal growth. Hypotheses to design related structures with improved biological properties are than builded. Each idea is then tested by the iterative synthesis and testing of novel compounds in various biological assays, searching for hits with better properties and defining useful and promising »lead« molecules. In parallel, molecular modeling and chemoinformatics experts can increase efficiency and decrease experimental costs by using different database filtering methods. In such a way, hits from HTS may be assessed before committing significant resource for chemical optimization. Joint efforts of these HTS experimental and modeling groups are the best way to speed up the process of finding a new useful hits and promising leads.Svrha HTS-a u farmaceutskoj industriji je identifikacija spojeva koji mogu poslužiti kao dobre polazne molekule u procesa razvoja lijeka iz novih kemijskih entiteta. Proučavanjem kemijske strukture takvih »hit« spojeva koji interagiraju s proteinom – metom, stručnjaci iz tog područja tragaju za strukturama poboljšanih bioloških svojstava. Svaka se ideja kasnije provjerava iterativnim postupkom sinteze i testiranja novih spojeva uporabom različitih metoda bioloških probira, kako bi se došlo do hitova s boljim svojstvima i do uporabivih i obećavajućih »lead« molekula. Istovremeno, molekularno modeliranje i kemoinformatika mogu povećati učinkovitosti i smanjenja troškova eksperimenata uporabom različitih metoda filtriranja baza spojeva. Na taj način, »hitovi« iz HTS-a mogu virtualno biti procijenjeni prije značajnog ulaganja resursa u kemijsku optimizaciju. Udruženi napori eksperimentalnih HTS grupa i grupa koje se bave molekularnim modeliranjem najbolji su način ubrzavanja procesa pronalaženja novih, uporabivih »hitova« i obećavajućih »leadova«

Kombinirani in silico i in vitro pristup pronalaženju spojeva s mogućim ljekovitim djelovanjem

The purpose of High Throughput Screening (HTS) in pharmaceutical industry is to identify, as soon as possible, compounds that are good starting points for successful new drug development process. Experts from this area study the chemical structures of so called »hit« compounds that have been found to interact with the target protein, interfere with proliferation of different types of cells or stop bacterial or fungal growth. Hypotheses to design related structures with improved biological properties are than builded. Each idea is then tested by the iterative synthesis and testing of novel compounds in various biological assays, searching for hits with better properties and defining useful and promising »lead« molecules. In parallel, molecular modeling and chemoinformatics experts can increase efficiency and decrease experimental costs by using different database filtering methods. In such a way, hits from HTS may be assessed before committing significant resource for chemical optimization. Joint efforts of these HTS experimental and modeling groups are the best way to speed up the process of finding a new useful hits and promising leads.Svrha HTS-a u farmaceutskoj industriji je identifikacija spojeva koji mogu poslužiti kao dobre polazne molekule u procesa razvoja lijeka iz novih kemijskih entiteta. Proučavanjem kemijske strukture takvih »hit« spojeva koji interagiraju s proteinom – metom, stručnjaci iz tog područja tragaju za strukturama poboljšanih bioloških svojstava. Svaka se ideja kasnije provjerava iterativnim postupkom sinteze i testiranja novih spojeva uporabom različitih metoda bioloških probira, kako bi se došlo do hitova s boljim svojstvima i do uporabivih i obećavajućih »lead« molekula. Istovremeno, molekularno modeliranje i kemoinformatika mogu povećati učinkovitosti i smanjenja troškova eksperimenata uporabom različitih metoda filtriranja baza spojeva. Na taj način, »hitovi« iz HTS-a mogu virtualno biti procijenjeni prije značajnog ulaganja resursa u kemijsku optimizaciju. Udruženi napori eksperimentalnih HTS grupa i grupa koje se bave molekularnim modeliranjem najbolji su način ubrzavanja procesa pronalaženja novih, uporabivih »hitova« i obećavajućih »leadova«

Obesity, microbiota and immunomodulation

Prekomjerna težina i pretilost predstavljaju rastući medicinski i socioekonomski problem modernog društva s brojnim zdravstvenim posljedicama. Prekomjerna težina povećava rizik od nastanka kroničnih i degenerativnih oboljenja, od metaboličkih, kardiovaskularnih i malignih bolesti preko podložnosti infekcijama do više stope smrtnosti. Masno tkivo pored uloge skladištenja energije ima i brojne endokrine i imunološke funkcije. Ono može utjecati na razvoj inzulinske neosjetljivosti, nastanak metaboličkog sindroma, a lučenjem adipokina, čimbenika stvorenih u masnim stanicama, doprinosi upalnim procesima, pa se i iz tog razloga pretilost smatra kroničnom upalnom bolešću. U razvoju pretilosti značajnu ulogu imaju crijevne mikrobiote, koje obavljaju važne metaboličke funkcije u probavi, apsorpciji i metabolizmu hranjivih tvari. Također, pravilan razvoj crijevnog epitela i imunološkog sustava pod izravnim je utjecajem mikrobiote u crijevima. Metabolička endotoksemija jedan je od načina kako mikrobiote doprinose upalnim procesima u organizmu. Uz farmakološke i kirurške pristupe liječenju pretilosti, balansiranom prehranom i modulacijom crijevne mikrobiote primjenom probiotika i prebiotika može se doprinijeti kontroliranom mršavljenju.Overweight and obesity represent a growing medical and socioeconomic problem of modern society with numerous consequences on human health. Overweight individuals are at increased risk for developing chronic and degenerative conditions, from metabolic, cardiovascular and malignant diseases to increased susceptibility to infections and higher mortality rates. Apart from being an energy storage, fat tissue also has numerous endocrine and immune functions. Fat tissue can induce insulin resistance, development of metabolic syndrome and by secreting adipokines directly contribute to inflammatory processes which makes obesity a chronic inflammatory disease. Gut microbiota have an important role in obesity development since they perform important metabolic functions in nutrients digestion, absorption and metabolism. Also, specific development of gut epithelia and immune system are under direct influence of gut microbiota. By inducing metabolic endotoxemia microbiota contributes to the development of inflammatory processes in the organism. Along with pharmacological and surgical treatments, controlled weight loss in obesity can also be achieved by balanced diet and by modulating gut microbiota with probiotics and prebiotics

Translating the Mediterranean diet: from chemistry to kitchen

The Mediterranean diet has been an area of popular and scientific intrigue for more than 30 years. Research has focused on both whole-diet compliance as well as individual component effects and many questions remain open as to the full spectrum of effects from this olive oil rich eating pattern. This paper summarizes key findings related to the Mediterranean diet including the health effects of olive oil as one tool in a whole-organism approach to modifying risk factors for cardiovascular disease, cancer, metabolic and other chronic illnesses. Suggestions for the utilization of these findings are summarized in a new »Holistic Food Pyramid«, optimized according to the basic principles of the Mediterranean diet and overall metabolic needs

Bovine Neutrophil Antibiotic Peptides and Their Precursors: Structure and Role in Innate Immunity

Four peptides were characterized in extracts of bovine neutrophil granules: an Arg-rich dodecapeptide, maintained in a cyclic structure by a disulfide bridge; a Trp-rich tridecapeptide named indo- licidin; and two 43- and 59 amino acids long peptides, named Bac5 and Bac7, with frequent repeats of the triplets Arg-Pro-Pro and Pro-Arg-Pro, respectively. The full length cDNA of the first three of these peptides was characterized recently. Sequence analysis showed that the prosequences of the predicted precursors of all the three peptides are highly identical and exhibited also a remarkable similarity to cathelin, a porcine inhibitor of cathepsin L. Purified proBacö actually proved in in vitro assays to inhibit cathepsin L, but not other cysteine proteinases such as cathepsin B. Unlike proBacö, proBac7 is selectively chemotactic to monocytes. Several fragments of Bac5 and Bac7 (from 6 to 35 residues) were synthesized by the Fmoc method. The results of antibacterial assays show that the N-terminal portion, the most cationic one in both Bac5 and Bac7, is essential for the antimicrobial activity and that the minimal length necessary to arrest the growth of susceptible bacteria is 18-20 residues

Diet and Respiratory Health

Disanje je proces izmjene plinova kroz pluća, ali i stanična oksidacija hrane u procesu metabolizma. Razumljiva je stoga činjenica da je zdravlje respiratornog sustava usko povezano s pravilnom prehranom. Osim energetske vrijednosti, hrana posjeduje i brojne farmakološke aktivnosti koje pridonose zdravlju respiratornog sustava. Pazeći na uravnoteženi unos hraniva i uzimajući u obzir respiratorne koeficijente pojedinih hranjivih tvari, može se uvelike pridonijeti oporavku od bolesti i bržem uspostavljanju funkcije dišnih organa. Posebnu pozornost potrebno je posvetiti unosu svježe hrane u obliku svježeg voća i povrća jer su posebno bogati vitaminima i mineralima te važnim biološki aktivnim tvarima (karotenoidi, polifenoli). Najnovija istraživanja također upućuju na povezanost respiratornog, imunosnog i probavnog sustava, posebice uravnotežene flore mikroorganizama (mikrobiote) za koju je dokazano da bitno može ublažiti simptome infekcija i alergija. No hrana ima i svoju psihološku komponentu te može pridonijeti boljem zdravlju živčanog sustava i tako posredno pozitivno utjecati na oporavak i ublažavanje simptoma respiratornih bolesti.Respiration is a process of gas exchange in the lungs, but also a cellular process of food metabolism for energy production. The health of the respiratory system is therefore tightly connected with the appropriate diet. Food not only provides energy for the body, but many food ingredients exert various biological effects which are important for health of the respiratory system. The function and health of the airways could be maintained by balancing the respiratory quotient of nutrients. Consuming plenty of fresh fruits and vegetables that are rich in vitamins, minerals and other nutraceuticals (carotenoids, polyphenols) is especially important. New research fi ndings have demonstrated the important connections between the immune system and the healthy digestive tract, in particular the balanced microbiota that can alleviate symptoms of infections and allergies. However, food also possesses psychological effects and may contribute to the improved health of the nervous system and consequently ease the symptoms of respiratory diseases