study of cyclic peptide furi inhibitor using Combinatorial chemistry.pptx

Content:
Introduction
History
Principle
Synthesis
Cyclic peptidic furin inhibitor.
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.Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but often structurally related molecules or materials. Combinatorial chemistry is especially common in CADD (Computer aided drug design) and can be done online with web based software, such as Molinspiration.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. In contrast to this approach, combinatorial chemistry offers the potential to make every combination of compound A1 to Am with compound B1 to Bn. Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when a researcher at Rockefeller University, Bruce Merrifield, started investigating the solid-state synthesis of peptides.

1. Combinatorial Chemistry By: Divya Ashok Dhule M.Pharm. (Pharmaceutical Chemistry) 1 st year Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440033

2. Title :International Journal Of Pharmaceutical Sciences And research Authors :Anas Rashad And Rumana Farhat Published on: 01 july 2013

3. Content: Introduction History Principle Synthesis Cyclic peptidic furin inhibitor

4. Introduction : Libraries are formed –structurally Similar & material similar. Molinspiration Common in CADD. 2n compounds are Formed where n- chemical steps Quikly Formed.

5. Professor pieczenik : first combinatorial library Pharmaceutical industries produce Over 100000 new & unique Compounds per year. Researcher create a virtual library. Researcher create a enumeration of all possible structure. Finding of novel drug is complex process. Accelerating the process. Help pharmaceutical industries.

6. History: It’s root seen in 1960, when Bruce Merrifield from Rockefeller university ,While he started investigating on solid phase synthesis of peptides. In 1984,H.Maria Geysen :developed this technique arrays of different peptides on separate support (pin shaped solid support). At Coronado Conference, geyson reported. Early in 1990’s synthesis of peptides & nucleotide libraries. In 1995,P.G.Schultz et. Al. – luminescent materials.

7. Principles: Large Number of Compounds formed. In Same vessels. With Simple methods. A +B -> AB Isolated & purified by Crystallisation, distillation.

8. In contrast to this approach, combinatorial chemistry offers the potential to make every combination of compound Al to An with compound B1 to Bn. Also applying other field :Semiconductor, Superconductors, polymers & Catalyst.

9. Combinatorial Synthesis on Solid Phase: In 1963,Merrifield got a Nobel prize. Insoluble, inert polymeric material – substrate—product form– cleaved . Developed chemical series : Chain of amino acid—peptides –cleaved -purified Resins for solid phase synthesis: Cross –linked Polystyrene Polyamide Linkers

10. Synthesis of Combinatorial library: Mix and split method by Furka scientist. Fig.96 Vessel

11. Parallel Solution phase synthesis:

12. Title : Cyclic Peptidic Furin Inhibitors Developed by Combinatorial Chemistry. Published on :15 March 2023

13. Cyclic peptidic Furin Inhibitors Developed by Combinatorial Chemistry Furin Human serine Protease Cellular Endoprotease PACE (Paired basic Amino acid Cleaving Enzyme) PCSKi9 (Proprotein Convertase Subtilosin /Kexin type 9 drugs)

14. Furin is responsible for development of pathological Conditions: Cancer Viral & Bacterial infection Atherosclerosis Neurodegenerative disorder Eg. HIV , influenza, Ebola So, Furin is regarded as potential target in various diseases

15. Furin enzyme Primary Structure of it’s Protein Substrates(motif)

16. Furin inhibitors: D- Arg based Peptides α-antitrypsin Portland Decanoyl –Arg-Chloromethylketones as a potential drug target in various viral diseases. Various Covalent & non Covalent Furin Inhibitors : 2,5-dideoxystreptamine derivatives polyarginines pepti- domimetics with a C-terminal decarboxylated 4-amidinoben- zylamide (4-amba) Engineering Serpin (α1-PDX)

17. SFTI -1 (Sunflower Trypsin inhibitors -1) Analogue . Fig:structure of Fittler inhibitors & SFTI( 1513Da ) MW: 500-5000 Da

18. Different screening Performed Different analogue Selecting most active inhibitors(attatching basic amino acid to their N. Termini) Stability( head to Tail cyclic analogue) General Formula of peptide amide library : Xaa- Xaa-Cys(&)-Xaa,-Xaa,-Ser-Ile-Pro-Pro-Ile-Cys(&)-Phe-NH2. Check the furin inhibitory activity in presence of fluorogenic Substrate : Pyr-Arg-Thr-Lys-Arg-AMC Where, Pyr is pyroglutamic acid AMC is 7-amino-4-methylcoumarin.

19. Deconvulation of peptide libraries against furin:

20. Conclusion: Application of a combinatorial chemistry approach resulted in strong, cyclic, peptidic furin inhibitors. They were designed based on the SFTI-1 framework, the widely recognized framework for engineering inhibitors of various, mostly serine, proteases. The library-derived structure of revealed here inhibitor I was highly similar to that of the inhibitor described by Fittler et al. (peptide FI).

21. References: Thomas , G. Furin at the Cutting Edge: From Protein Traffic to Embryogenesis and Disease. Nat. Rev. Mol. Cell Biol. 2002, 3 (10), 753-766.
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