196 research outputs found
Virtual chemical reactions for drug design
No full textTwo methods for the fast, fragment-based combinatorial molecule assembly were developed. The software COLIBREE® (Combinatorial Library Breeding) generates candidate structures from scratch, based on stochastic optimization [1]. Result structures of a COLIBREE design run are based on a fixed scaffold and variable linkers and side-chains. Linkers representing virtual chemical reactions and side-chain building blocks obtained from pseudo-retrosynthetic dissection of large compound databases are exchanged during optimization. The process of molecule design employs a discrete version of Particle Swarm Optimization (PSO) [2]. Assembled compounds are scored according to their similarity to known reference ligands. Distance to reference molecules is computed in the space of the topological pharmacophore descriptor CATS [3]. In a case study, the approach was applied to the de novo design of potential peroxisome proliferator-activated receptor (PPAR gamma) selective agonists. In a second approach, we developed the formal grammar Reaction-MQL [4] for the in silico representation and application of chemical reactions. Chemical transformation schemes are defined by functional groups participating in known organic reactions. The substructures are specified by the linear Molecular Query Language (MQL) [5]. The developed software package contains a parser for Reaction-MQL-expressions and enables users to design, test and virtually apply chemical reactions. The program has already been used to create combinatorial libraries for virtual screening studies. It was also applied in fragmentation studies with different sets of retrosynthetic reactions and various compound libraries
Photochemistry in Medicinal Chemistry and Chemical Biology
No full text: Photochemistry has emerged as a transformative force in organic chemistry, significantly expanding the chemical space accessible for medicinal chemistry. Light-induced reactions enable the efficient synthesis of intricate organic structures and have found applications throughout the different stages of the drug discovery and development processes. Moreover, photochemical techniques provide innovative solutions in chemical biology, allowing precise spatiotemporal drug activation and targeted delivery. In this Perspective, we highlight the already numerous remarkable applications and the even more promising future of photochemistry in medicinal chemistry and chemical biology
Rational, computer-aided design of multi-target ligands : poster presentation from 6th German Conference on Chemoinformatics, GCC 2010, Goslar, Germany. 7-9 November 2010
No full textOver the past two decades the “one drug – one target – one disease” concept became the prevalent paradigm in drug discovery. The main idea of this approach is the identification of a single protein target whose inhibition leads to a successful treatment of the examined disease. The predominant assumption is that highly selective ligands would avoid unwanted side effects caused by binding to secondary non-therapeutic targets. In recent years the results of post-genomic and network biology showed that proteins rarely act in isolated systems but rather as a part of a highly connected network [1]. In addition this connectivity leads to more robust systems that cannot be interfered by the inhibition of a single target of that network and consequently might not lead to the desired therapeutic effect [2]. Furthermore studies prove that robust systems are rather affected by weak inhibitions of several parts than by a complete inhibition of a single selected element of that system [3]. Therefore there is an increasing interest in developing drugs that take effect on multiple targets simultaneously but is concurrently a great challenge for medicinal chemists. There has to be a sufficient activity on each target as well as an adequate pharmacokinetic profile [4]. Early design strategies tried to link the pharmacophors of known inhibitors, however these methods often lead to high molecular weight and low ligand efficacy. We present a new rational approach based on a retrosynthetic combinatorial analysis procedure [5] on approved ligands of multiple targets. These RECAP fragments are used to design a large combinatorial library containing molecules featuring chemical properties of each ligand class. The molecules are further validated by machine learning models, like random forests and self-organizing maps, regarding their activity on the targets of interest
SBE13, a newly identified inhibitor of inactive polo-like kinase 1
No full textPoster presentation at 5th German Conference on Cheminformatics: 23. CIC-Workshop Goslar, Germany. 8-10 November 2009 Protein kinases are important targets for drug development. The almost identical protein folding of kinases and the common co-substrate ATP leads to the problem of inhibitor selectivity. Type II inhibitors, targeting the inactive conformation of kinases, occupy a hydrophobic pocket with less conserved surrounding amino acids. Human polo-like kinase 1 (Plk1) represents a promising target for approaches to identify new therapeutic agents. Plk1 belongs to a family of highly conserved serine/threonine kinases, and is a key player in mitosis, where it modulates the spindle checkpoint at metaphase/anaphase transition. Plk1 is over-expressed in all today analyzed human tumors of different origin and serves as a negative prognostic marker in cancer patients. The newly identified inhibitor, SBE13, a vanillin derivative, targets Plk1 in its inactive conformation. This leads to selectivity within the Plk family and towards Aurora A. This selectivity can be explained by docking studies of SBE13 into the binding pocket of homology models of Plk1, Plk2 and Plk3 in their inactive conformation. SBE13 showed anti-proliferative effects in cancer cell lines of different origins with EC50 values between 5 microM and 39 microM and induced apoptosis. Increasing concentrations of SBE13 result in increasing amounts of cells in G2/M phase 13 hours after double thymidin block of HeLa cells. The kinase activity of Plk1 was inhibited with an IC50 of 200 pM. Taken together, we could show that carefully designed structure-based virtual screening is well-suited to identify selective type II kinase inhibitors targeting Plk1 as potential anti-cancer therapeutics
In silico polypharmacology: retrospective recognition vs. rational design : From 9th German Conference on Chemoinformatics. Fulda, Germany. 10-12 November 2013
No full textOral presentation 9th German Conference on Chemoinformatics Fulda, Germany. 10-12 November 2013.
The "one drug – one target – one disease" paradigm in drug discovery has been reconsidered during the last decade..
Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade
No full textChronic inflammation and pain is a major global health problem, and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most frequently prescribed drugs and common option for the treatment of inflammatory pain. However, they have the potential to cause serious complications, such as gastrointestinal (GI) lesions, bleeding and cardiovascular (CV) problems. NSAIDs exert their anti-inflammatory, analgesic and anti-pyretic actions by inhibiting the cyclooxygenases (COX)-1 and COX-2, key enzymes of the arachidonic acid (AA) cascade. However, not all the AA products or their receptors are pro-inflammatory. Therefore, given the multifaceted interactions of these lipid mediators where a single precursor can trigger multiple events with synergic or opposed function, it is easy to predict that any perturbation of this interplay will cause several unavoidable side effects.
Today, we do not have a truly safe NSAID that minimizes GI damage and CV toxicity. One possibility to interfere with this intricate network, while trying to keep its fine balance, is to develop molecules affecting several targets. Different strategies have been proposed for a multitargeted intervention at different levels of the AA cascade, like inhibition of multiple upstream enzymes, such as COX, 5-lipoxygenase, or even soluble epoxide hydrolase and prostaglandin E synthase. Alternative strategies are more focused in the inhibition of targets downstream in the metabolic pathway, such as thromboxane synthase and/or blocking selective receptors. In this review we will briefly summarize the new strategies that have been proposed for a multitargeted pharmacological intervention on this metabolic cascade aimed at developing novel anti-inflammatory therapeutics
Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors
No full textThe transcriptional regulator FUSE binding protein 1 (FUBP1) is aberrantly upregulated in various malignancies, fulfilling its oncogenic role by the deregulation of critical genes involved in cell cycle control and apoptosis regulation. Thus, the pharmaceutical inhibition of this protein would represent an encouraging novel targeted chemotherapy. Here, we demonstrate the identification and initial optimization of a pyrazolo[1,5a]pyrimidine-based FUBP1 inhibitor derived from medium throughput screening, which interferes with the binding of FUBP1 to its single stranded target DNA FUSE. We were able to generate a new class of FUBP1 interfering molecules with in vitro and biological activity. In biophysical assays, we could show that our best inhibitor, compound 6, potently inhibits the binding of FUBP1 to the FUSE sequence with an IC50value of 11.0 μM. Furthermore, hepatocellular carcinoma cells exhibited sensitivity towards the treatment with compound 6, resulting in reduced cell expansion and induction of cell death. Finally, we provide insights into the corresponding SAR landscape, leading to a prospective enhancement in potency and cellular efficacy.Fil: Hauk, Stefanie. Georg Speyer-haus; AlemaniaFil: Hiesinger, Kerstin. Goethe Universitat Frankfurt; AlemaniaFil: Khageh Hosseini , Sabrina. Georg Speyer-haus; AlemaniaFil: Achenbach, Janosch. Goethe Universitat Frankfurt; AlemaniaFil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Goethe Universitat Frankfurt; Alemania. German Cancer Consortium; AlemaniaFil: Proschak, Ewgenij. University Hospital Frankfurt; AlemaniaFil: Zörnig, Martin. Georg Speyer-haus; AlemaniaFil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemani
Evaluierung neuer Substanzen zur Hemmung der Leukotrienbiosynthese
No full textViele Erkrankungen resultieren aus einer gestörten Entzündungsreaktion. Kortikosteroide und NSAR sind zurzeit die Mittel der Wahl, können bei Langzeiteinnahme aber zu schweren Nebenwirkungen führen. Deswegen sucht man nach weiteren Therapeutika, bei denen nicht nur proinflammatorische Mediatoren gehemmt, sondern auch die für die Geweberegeneration wichtigen antiinflammatorischen Lipidmediatoren vermehrt gebildet werden. In meiner Arbeit wurden 38 Substanzen (ALR-1 bis ALR-38) auf ihren Einfluss in der Leukotrien- und Prostaglandinbiosynthese untersucht, um potenzielle Wirkstoffe für die pharmakologische Entzündungshemmung herauszufiltern. Im ersten Schritt wurden durch Experimente an isolierter und in PMNL exprimierter 5-Lipoxygenase (5-LO) wirksame Inhibitoren dieses Enzyms ermittelt. ALR-6 und ALR-27 zeigten sich dabei als einzige Stoffe mit einem ausreichenden inhibitorischen Potenzial. Am isolierten Enzym konnten jedoch beide Stoffe keine hemmende Wirkung erzielen, jedoch konnte in PMNL eine verminderte Syntheserate an 5-LO-Produkten nachgewiesen werden. Es konnte außerdem eine Wirkung auf die Phospholipase A2 ausgeschlossen werden, da trotz Zufuhr exogener Arachidonsäure eine Hemmung der 5-LO stattfand. Für Enzyme im Prostaglandinstoffwechsel (mPGES-1, sEH) ergab sich für beide Substanzen keine deutliche Inhibition. Durch die Analyse des Lipidmediatorprofils in M1- und M2-Makrophagen konnte nachgewiesen werden, dass ALR-6 und ALR-27 nicht nur hemmend in die Leukotrienbiosynthese eingreifen, sondern auch einen positiven Einfluss auf die Resolution der Entzündung haben. Vor allem durch ALR-6 konnte ein Anstieg der antiinflammatorisch wirksamen Lipoxine in antiinflammatorisch wirksamen M2-Makrophagen dokumentiert werden. Die Wirkung muss nun auch in in-vivo-Experimenten und klinischen Studien nachgewiesen werden, damit beide Wirkstoffe schlussendlich als brauchbare Therapeutika Verwendung finden können
- …
