ABDUL RAZZAQ ORD

SEMINAR ONCOMBINATORIAL CHEMISTRY : 

COMBINATORIAL CHEMISTRY 1 SEMINAR ONCOMBINATORIAL CHEMISTRY ABDUL RAZZAQ M.PHARM 1ST PHARMA CHEM.DEPT LUQMAN COLLEGE OF PHARMACY, GULBARGA PRESENTED BY -:

TOPICS : 

COMBINATORIAL CHEMISTRY 2 TOPICS Introduction to combinatorial chemistry. Introduction to combinatorial library. Concept and Terms. Parallel organic synthesis technology.

Introduction-: : 

COMBINATORIAL CHEMISTRY 3 Introduction-: Finding of novel drug is the very complex process. Historically the main source of biologically active compound used in drug discovery programs has been natural product, isolated from plant ,animal or fermentation sources. To solve this complex process, one of the important method develop by researchers in Pharma industry to reduced time & costs associated with producing effective & competitive new drugs called combinatorial chemistry. This new technology helps to find new drugs quickly, save significant money in preclinical development costs & ultimately change their fundamental approach to drug discovery. It is the technique by which large no. of molecule synthesis in a time & submitted for pharmaceutical assay. The large range of analogue synthesis using same reaction condition, same reaction vessels. Chemist can synthesis thousand of compound in one time instead of preparing only a few by simple methodology.

Definition -: : 

COMBINATORIAL CHEMISTRY 4 Definition -: Combinatorial chemistry is a young branch of science which deals with large no of structurally distinct molecule may be synthesized at the same time and these assayed to identify the most promising compound for further development by spot screening. OR Combinatorial chemistry is define as the systematic and repetitive covalent connection of a set of different building blocks of varying structure to each other to yield a large array of diverse molecular entities

Ideas of combinatorial chemistry- : 

COMBINATORIAL CHEMISTRY 5 Ideas of combinatorial chemistry- Is to make a large numbers of chemistry variant all at one time. To test them for bio activity, binding with a target or other desired properties. Then to isolate & identify the most promising compound for further development Combinatorial chemistry includes many research area – New analytical method New computer modeling Data base related challenges New synthetic approach New type of reagent acid also New type of assay

PRINCIPLE OF COMBINATORIAL CHEMISTRY-: : 

COMBINATORIAL CHEMISTRY 6 PRINCIPLE OF COMBINATORIAL CHEMISTRY-: In the past, chemists have traditionally made one compound at a time. For example compound A would have been reacted with compound B to give product AB, which would have been isolated after reaction work up and purification through crystallization, distillation, or chromatography. A + B → AB Orthodox synthesis In contrast to this approach, combinatorial chemistry offers the potential to make every combination of compound A1 to An with compound B1 to Bn. The range of combinatorial techniques is highly diverse, and these products could be made individually in a parallel or in mixtures, using either solution or solid phase techniques. Whatever the technique used the common denominator is that productivity has been amplified beyond the levels that have been routine for the last hundred years.

COMBINATORIAL LIBRARIES-: : 

COMBINATORIAL CHEMISTRY 7 COMBINATORIAL LIBRARIES-: The collection of these finally synthesized compounds together is called as combinatorial library. Where as collection of separate single substances are called as arrays. Using traditional method of chemical synthesis the potentional drug substance are synthesize once at a time then purified then structure have to be confirmed & then testing for their effectiveness as drugs so it would take many years to build such library. Library can be prepared by two method - 1. Parallel synthesis 2. Split-mix synthesis

1. Parallel Synthesis ( Orthodox synthesis )-: : 

COMBINATORIAL CHEMISTRY 8 1. Parallel Synthesis ( Orthodox synthesis )-: In parallel synthesis different compound are synthesize in separate vessel without remixing , often in a automated machine . Unlike the split synthesis which required solid support, parallel synthesis can be done either on solid support or in a solution. A commonly used format for parallel synthesis is 96 – well micro titer plate . Robotic instrumentation is used to add different reagent to separate well of a micro titer plate in predefined manner to produce combinatorial libraries .It is from the library are identify by the position on the well plate Multiple parallel synthesis restrict the production of compound to smaller numbers than split & pool synthesis. However greater quantities of compound are created & there is no need to deconvulate or tag the individuals compound .Also since they are plated as a single compound as per well, activity measured from screening can be correlated directly to the individual compounds for subsequent (SAR) study. There are two methods are adapted for parallel synthesis Spatially separate synthesis Spatially addressable synthesis

Slide 9: 

COMBINATORIAL CHEMISTRY 9 + Illustrative fig. of spatially separate synthesis It yields large quantities of a relatively small number of compound. Up to 10000 compound can be synthesized at a time. Assays can be done on individual compound. So it is void of serious interferences and complications that can arise with spilt synthesis.

Spatially addressable parallel synthesis : 

COMBINATORIAL CHEMISTRY 10 Spatially addressable parallel synthesis In this method the libraries are synthesized in arrays on microchips and all the compound in chip are assayed simultaneously for finding the activity Up to 100000 compound can be prepared at a time. Researcher had prepared up to 65000 compound on 1sq.cm. area of microchip. By use of soluble fluorescently labeled receptor, percentage binding to different locations can be bind by epifluorescence microscopy. Recently the library has been developed on whatmann filter paper also.

2. Split-mix synthesis : 

COMBINATORIAL CHEMISTRY 11 2. Split-mix synthesis In split & pool synthesis method microscopic resin beads are divided into N microscopic reaction vessels , one for each monomer library ( N would be 20 for peptide synthesis with 20 different naturally occurring amino acid ). The first monomer is coupled to resin & the beads in each reaction vessel are reported the cycle of divide couple & repooled – repeated several times ( N times to create an N –library ) using suitable deprotecting group, each time a new monomer of each of the N-mer at each position in combinatorial library .It is an example of solid phase synthesis method .This method is especially suitable for peptide & oligo nucleotide libraries . Resin beads generally used in cross linked polystyrene (styrene is cross linked with 1% divinely benzene).

Comparison : 

COMBINATORIAL CHEMISTRY 12 Comparison

Applications- : 

COMBINATORIAL CHEMISTRY 13 Applications- Finding right combination of drug molecule. Synthesis of small molecule libraries. Applications of antibody libraries obtained by combinatorial chemistry. Discovery of enzymes inhibitors through combinatorial chemistry. Combinatorial chemistry –tool for lead optimization. Combining structure- based drug design and combinatorial chemistry for the rapid lead discovery. Small peptides can mimic erythrism protein. Combinatorial chemistry spawns new software system to manage flood of information. A qualitative and quantitative characterization of known drug database through combinatorial libraries.

Slide 14: 

COMBINATORIAL CHEMISTRY 14 Thank you