Drug discovery

Résumé

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy. Modern drug discovery involves the iden

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https://en.wikipedia.org/wiki/Drug_discovery

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On the role of water density fluctuations in the inhibition of a proton channel

Lucie Monique Françoise Delemotte

Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.

Natl Acad Sciences2016

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Breakthroughs in health care over the coming decades may well consist of cell based therapeutics, potentially allowing the repair and replacement of damaged tissues and organs. Recently developed induced pluripotency methods as well as advances in stem cell biology show hope of such a reality. But such prospects come with the need to have a robust understanding and control over cell development and differentiation processes. Cells in the body develop in tightly controlled and specialized micro-environments that provide many complex cues and interactions that guide cell fate by directing gene expression. But current cell culture techniques that are most widely used to study the cell outside the body have not significantly changed from when first started over a century ago, using simple containers and flasks with plastic surfaces. Many studies have shown that three-dimensions (3D) over conventional 2D cell culture alone, showed to have increased levels of cell organization, morphology and function. By combining novel biomaterials and microfabrication methods, this project aims to create a tool that allows the study of cells within a simplified 3D environment. With the potential to build up the physical and soluble complexity of this environment in a tailor made fashion, a "dissection" of the functions and influences of external factors may be understood. Such a tool can also be used for the development of cell based models, highly relevant for drug discovery application as well as potentially for the development of cell based therapeutics. We have developed a novel microfluidic 3D cell culture platform that allows controlled soluble factor perfusion in an enzymatically formed and cell responsive PEG-based hydrogel. Soft lithographic processes were used to mold microchannels on a layer of hydrogel. In a second step, a flat hydrogel layer is placed on top to enclose and form the microchannels . The system allows the control over soluble factor delivery and it is able to perform long-term cell culture and generate user controlled gradients of soluble factors. With continuous perfusion, metabolic waste is constantly removed and cells are supplied with fresh medium. The platform also can allow creation of tailor made environments building up complexity in a controlled fashion. Higher throughput is also achieved by arraying individual culture chambers. The device was applied towards the culture of mouse embryonic stem cells (mESC) in order to demonstrate their self-renewal capacity on the microfluidic platform. The effects of some cytokine factors were also studied. Meaningful readouts such as fluorescence are easily used for analysis and cells can possibly be extracted from the device for further downstream analysis and processing. Through this device we show that microfluidics technologies combined with biomaterials enables the creation of platforms that are biologically relevant for the study and understanding of cell processes from cancer to stem cell development, processes which are fundamentally regulated by interactions with the microenvironment. The platform developed may also be used to develop human tissue models perhaps more relevant than current animal based testing, providing new tools for drug development and also potentially new approaches for developing cell based therapeutics

2009

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The global emergence of multi-drug resistant bacteria invokes an urgent and imperative necessity for the identification of novel antimicrobials. The general lack of success in progressing novel chemical entities from target-based drug screens have prompted calls for radical and innovative approaches for drug discovery. Recent developments in chemical biology and target deconvolution strategies have revived interests in the utilization of whole-cell phenotypic screens and resulted in several success stories for the discovery and development novel drug candidates and target pathways. In this review, we present and discuss recent chemical biology approaches focusing on the discovery of novel targets and new lead molecules for the treatment of human bacterial and protozoan infections.

Pharmaceutical Soc Korea2015

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2009