Combinatorial Chemistry and Technology

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People involved in UQC research projects do not participate in collaborative projects with companies. Technological offer Medicinal chemistry Heterocyclic and condensation chemistry Synthesis of peptides, dendrimers, natural products, chemical biology tools Bioconjugation chemistry Design and synthesis of small to medium-sized chemical libraries compounds , both solid-phase and in solution, and microwave assisted synthesis, using parallel automatic and semi-automatic synthesis Development of analytical methods HPLC, HPLC-MS, HR-TLC Development and optimization of reactions Isolation of natural products, biodirected fractionation We can develop collaborative projects with companies with full dedicated people specially contracted for them.

Our productivity and efficacy is internally measured to give the best service. Miriam Royo. Access Procedures. Combinatorial chemistry. Assurance of quality. QSAR formalizes what is experimentally known about how a given protein interacts with some tested compounds. As an example, it may be known from previous experiments that the protein under investigation shows signs of activity against one group of compounds, but not against another group.

In terms of the lock and key metaphor, we do not know what the lock looks like, but we do know which keys work, and which do not. In order to build a QSAR model for deciding why some compounds show sign of activity and others do not, a set of descriptors are chosen. These are assumed to influence whether a given compound will succeed or fail in binding to a given target.

Typical descriptors are parameters such as molecular weight, molecular volume, and electrical and thermodynamical properties. QSAR models are used for virtual screening of compounds to investigate their appropriate drug candidates descriptors for the target The requirements for;. Alternatively, combinatorial chemistry in solution or on solid support, is being developed to increase the efficiency of organic syntheses. Furthermore, successful applications of such methods leading to the discovery of therapeutic candidates have been reported.

The synthesis of complex small molecules on solid support using different organic reactions such as multi-step sequential substitution reactions, multi-component condensation reactions and pharmacophore modifying reactions has been accomplished. Beta-lactams; hydantoin imides and thioimides; imidazoles; N-acyl-alpha-amino amides, esters, acids; oxazoles; phosphonates alpha-hydroxy, alpha-amino, alpha-acylamino ; phosphinates; pyrroles; tetra-substituted 5 membered ring lactams; tetra-substituted 6 membered ring lactams and tetrazoles are synthesized on solid support using a wide range of organic transformations including: acylations; aldol condensations; alkylations; Claisen couplings; Heck reactions; heterocycle forming reactions such as condensations, dipolar cycloadditions, annulations, etc.

The final products are cleaved into a standard 96 well microtiter plate, one compound per well. Each plate can be directly submitted for high throughput screening as well as quantitative and semi-quantitative analysis in order to assess purity, identity and yield of each compound synthesized The nature of substrate; the mechanism of target-substrate interaction; related literature information; 3-D structural information.

In general, the method of synthesis is designed to allow full control over each of the individual substituents.

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In general the inputs are chosen to be commercially available. On occasion, inputs are synthesized for specific cases, fully aware that input synthesis has the potential to dramatically reduce the efficiencies of the combinatorial approach. A screening facility typically holds a library of stock plates, whose contents are carefully catalogued, and each of which may have been created by the lab or obtained from a commercial source. These stock plates themselves are not directly used in experiments; instead, separate assay plates are created as needed.

An assay plate is simply a copy of a stock plate, created by pipetteing a small amount of liquid often measured in nanoliters from the wells of a stock plate to the corresponding wells of a completely empty plate Otherwise, a specialized automated analysis machine can run a number of experiments on the wells such as shining polarized light on them and measuring reflectivity, which can be an indication of protein binding.

In this case, the machine outputs the result of each experiment as a grid of numeric values, with each number mapping to the value obtained from a single well. A high-capacity analysis machine can measure dozens of plates in the space of a few minutes like this, generating thousands of experimental datapoints very quickly. Depending on the results of this first assay, the researcher can perform follow up assays within the same screen by "cherrypicking" liquid from the source wells that gave interesting results known as "hits" into new assay plates, and then re-running the experiment to collect further data on this narrowed set, confirming and refining observations.

HTS research is one of the fields which have a feature described by Eisenstein as follows: soon, if a scientist does not understand some statistics or rudimentary data-handling technologies, he or she may not be considered to be a true molecular biologist and thus will simply become a dinosaur. Effective analytic QC methods serve as a gatekeeper for excellent quality assays. In a typical HTS experiment, a clear distinction between a positive control and a negative reference such as a negative control is an index for good quality.

Many quality assessment measures have been proposed to measure the degree of differentiation between a positive control and a negative reference. Signal-to-background ratio, signal-to-noise ratio, signal window, assay variability ratio, and Z-factor have been adopted to evaluate data quality. For hit selection in primary screens without replicates, the easily interpretable ones are average fold change, mean difference, percent inhibition, and percent activity.

However, they do not capture data variability effectively. The z-score method or SSMD, which can capture data variability based on an assumption that every compound has the same variability as a negative reference in the screens. However, outliers are common in HTS experiments, and methods such as z-score are sensitive to outliers and can be problematic. One issue with the use of t-statistic and associated p-values is that they are affected by both sample size and effect size.

They come from testing for no mean difference, thus are not designed to measure the size of compound effects. For hit selection, the major interest is the size of effect in a tested compound. SSMD directly assesses the size of effects. SSMD has also been shown to be better than other commonly used effect.

The population value of SSMD is comparable across experiments and thus we can use the same cutoff for the population value of SSMD to measure the size of compound effects.


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Techniques for increased throughput and efficiency unique distributions of compounds across one or many plates can be employed to increase either the number of assays per plate, or to reduce the variance of assay results, or both. The simplifying assumption made in this approach is that any N compounds in the same well will not typically interact with each other, or the assay target, in a manner that fundamentally changes the ability of the assay to detect true hits. For example, imagine a plate where compound A is in wells , compound B is in wells , and compound C is in wells In an assay of this plate against a given target, a hit in wells 2, 3, and 4 would indicate that compound B is the most likely agent, while also providing three measurements of compound B's efficacy against the specified target.

Commercial applications of this approach involve combinations in which no two compounds ever share more than one well, to reduce the second-order possibility of interference between pairs of compounds being screened. In researchers developed a silicon sheet of lenses that can be placed over microfluidic arrays to allow the fluorescence measurement of 64 different output channels simultaneously with a single camera.

This process can analyze , drops per second. Northwestern University's High Throughput Analysis Laboratory supports target identification, validation, assay development, and compound screening. In the United States, the National Institute of Health or NIH has created a nationwide consortium of small molecule screening centers that has been recently funded to produce innovative chemical tools for use in biological research.

One-molecule-at-a-time discovery strategies, many researchers see combinatorial chemistry as a better way to discover new drugs, catalysts, and materials. Compared with conventional one-molecule-at-a-time discovery strategies, many researchers see combinatorial chemistry as a better way to discover new drugs, catalysts, and materials. It is a method for reacting a small number of chemicals to produce simultaneously a very large number of compounds, called libraries, which are screened to identify useful products such as drug candidates and a method in which very large numbers of chemical entities are synthesized by condensing a small number of reagents together in all combinations defined by a small set of reactions.

Article Information Sr No: 8. Download: Cited By: DOI: Colony, Hyderabad, Andhra Pradesh, India ABSTRACT: Combinatorial chemistry is a new methodology by which we can simultaneously synthesize a number of possible compounds that could produce simultaneously a very large number of compounds, called libraries. Parallel and orthodox synthesis is compared below; FIG. Cross-linked Polystyrene: Lightly cross-linked gel type polystyrene GPS Figure has been most widely used due to its common availability and inexpensive cost.

GPS beads which are functionalised with chloromethyl-, aminomethyl-, and a variety of linkers are commercially available from a variety of sources. A prominent characteristic of GPS beads is their ability to absorb large relative volumes of certain organic solvents swelling. This swelling causes a phase change of the bead from a solid to a solvent-swollen gel, and therefore, the reactive sites are accessed by diffusion of reactants through a solvent-swollen gel network. DMF, or N-methyl pyrrolidinone.

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The linker is a specialised protecting group, in that much of the time, the linker will tie up a functional group, only for it to reappear at the end of the synthesis. The linker must not be affected by the chemistry used to modify or extend the attached compound. And finally the cleavage step should proceed readily and in a good yield. The best linker must allow attachment and cleavage in quantitative yield This DNA encoding concept had in fact been demonstrated in some of the first combinatorial library preparation methods ever reported — those utilising filamentous phage particles.

In this approach, libraries of peptides are prepared biochemically from the cloning and expression of random sequence oligonucleotides. Pools of oligonucleotides encoding the peptides of interest are interested into an appropriate expression system, where upon translation the resulting peptides are synthesized as fusion proteins. One of the common expression systems fuses these sequences to the gene III or the gene VIII coat protein of filamentous phage particles. Each viral particle contains a unique DNA sequence that encodes only a simple peptide. After screening a library in a given biological system, any viral particles displaying active peptides are isolated and the structure of the active peptides is elucidated by sequencing their encoding DNAs.

A distinct disadvantage with this approach is that the molecular diversity of such systems is limited to peptides, and amino acids that compose these peptides are restricted to the 20 encoded by genes. Peptide Tag: Zuckermann et al. Since the Edman degradation requires a free N-terminus, this peptide as code strategy could also be used to encode other peptide by acylating the N-terminus of the binding peptide strand, and leaving a free amine at the coding peptide terminus. To accommodate the parallel synthesis of both binding and coding peptides, an orthogonally protected bifunctional linker was employed that contained both acid and base sensitive protecting groups.

Mass Encoding: The entire reported single bead encoding schemes require the cosynthesis of a suitable tagging moiety to record the synthetic history of each compound prepared in the library. This is inherently inefficient, since each unique compound could encode for itself if appropriate analytical techniques such as 1H, 13C NMR could be used to assign structures to ligands present in the amounts provided by single beads.

This testing is often done in so called high-thoughput screening HTS facilities. Compound libraries are commercially available in sizes of up to several millions of compounds. The most promising compounds obtained from the screening are called hits — these are the compounds that show binding activity towards the target. Some of these hits are then promoted to lead compounds — candidate structures which are further refined and modified in order to achieve more favorable interactions and less side-effect.

Drug Discovery Methods: The following are methods for finding a drug candidate, along with their pros and cons: Virtual screening VS based on the computationally inferred or simulated real screening; The main advantages of this method compared to laboratory experiments are: Low costs, no compounds have to be purchased externally or synthesized by a chemist; It is possible to investigate compounds that have not been synthesized yet; Conducting HTS experiments is expensive and VS can be used to reduce the initial number of compounds before using HTS methods; Huge amount of chemicals to search from.

The number of possible virtual molecules available for VS is exceedingly higher than the number of compounds presently available for HTS; The disadvantage of virtual screening is that it cannot substitute the real screening. The real screening, such as high-throughput screening HTS , can experimentally test the activity of hundreds of thousands of compounds against the target a day. This method provides real results that are used for drug discovery.

However, it is highly expensive. They can be used to assist in building hypotheses about desirable chemical properties when designing the drug and, moreover, they can be used to refine and modify drug candidates. Thus, libraries of compounds can be created for biological screening and perform medicinal chemistry optimization strategies ultimately leading to compounds for human clinical trials FIG. Design of Pharmacophore: The design of the pharmacophore basis of a particular library is driven by the nature of the biological target of interest.

The following types of information are considered, if available: The biology of the target enzyme or receptor; The nature of substrate; the mechanism of target-substrate interaction; related literature information; 3-D structural information. High-Throughput Screening HTS : High-throughput screening HTS is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry.

Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a researcher to quickly conduct millions of chemical, genetic or pharmacological tests. Through this process one can rapidly identify active compounds, antibodies or genes which modulate a particular biomolecular pathway. The results of these experiments provide starting points for drug design and for understanding the interaction or role of a particular biochemical process in biology. Assay Plate Preparation: The key labware or testing vessel of HTS is the microtiter plate: a small container, usually disposable and made of plastic that features a grid of small, open divots called wells.

Modern circa microplates for HTS generally have either , , or wells. These are all multiples of 96, reflecting the original 96 well microplate with 8 x 12 9mm spaced wells.

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Most of the wells contain experimentally useful matter, depending on the nature of the experiment. This could be an aqueous solution of dimethyl sulfoxide DMSO and some other chemical compound, the latter of which is different for each well across the plate. It could also contain cells or enzymes of some type The other wells may be empty, intended for use as optional experimental controls.

Reaction observation: To prepare for an assay, the researcher fills each well of the plate with some logical entity that he or she wishes to conduct the experiment upon, such as a protein, or an animal embryo. After some incubation time has passed to allow the biological matter to absorb, bind to, or otherwise react or fail to react with the compounds in the wells, measurements are taken across all the plate's wells, either manually or by a machine.

Manual measurements are often necessary when the researcher is using microscopy to for example seek changes or defects in embryonic development caused by the wells' compounds, looking for effects that a computer could not easily determine by itself. Typically, an integrated robot system consisting of one or more robots transports assay-microplates from station to station for sample and reagent addition, mixing, incubation, and finally readout or detection.

An HTS system can usually prepare, incubate, and analyze many plates simultaneously, further speeding the data-collection process. HTS robots currently exist which can test up to , compounds per day. Automatic colony pickers pick thousands of microbial colonies for high throughput genetic screening. The term uHTS or ultra-high throughput screening refers to screening in excess of , compounds per day.

Experimental Design and Data Analysis: With the ability of rapid screening of diverse compounds such as small molecules or siRNAs to identify active compounds, HTS has led to an explosion in the rate of data generated in recent years. Consequently, one of the most fundamental challenges in HTS experiments is to glean biochemical significance from mounds of data, which relies on the development and adoption of appropriate experimental designs and analytic methods for both quality control and hit selection. The development of high-quality HTS assays requires the integration of both experimental and computational approaches for quality control QC.

The process of selecting hits is called hit selection. The analytic methods for hit selection in screens without replicates usually in primary screens differ from those with replicates usually in confirmatory screens. For example, the z-score method is suitable for screens without replicates whereas the t-statistic is suitable for screens with replicate.

The calculation of SSMD for screens without replicates also differs from that for screens with replicates. Drops of fluid separated by oil replace microplate wells and allow analysis and hit sorting while reagents are flowing through channels. It still takes a highly specialized and expensive screening lab to run an HTS operation, so in many cases a small-to-moderately sized research institution will use the services of an existing HTS facility rather than set up one for it. There is a trend in academia to be their own drug discovery enterprise High-throughput screening goes to school.

These facilities, which normally are only found in industry, are now increasingly be found as well at universities. Light-directed, spatially addressable parallel chemical synthesis. Science PMID Gordeeva et al. Xiang et al. Hanak, J. Sci, Combinatorial Characterization, , 5, Combinatorial methods for development of sensing materials, Springer, ISBN Mirsky, V. Kulikov, Q. Hao, O. Koinuma et al. Andrei Ionut Mardare et al.

Cawse, Ed. Newman and G. Feher and J. Campian, J. Chou, M.


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