FRAGMENT BASED DRUG DESIGN .pptx

fBDD

1. FRAGMENT BASED DRUG DESIGN RAJIV GANDHI PROUDYOGIKI VISHWAVIDYALAYA SCHOOL OF PHARMACEUTICAL SCIENCE PRESENTED BY ;- YASH KANCHANWAR SUBJECT ;- CADD ROLL NO. ;- 0001PY23MP11 BRACH;- PHARMACEUTICAL CHEMISTRY

2. CONTENT 1] FBDD 2] FRAGMENT DEFINATION 3] RULES 4] LEAD EFFICIENCY 5] CONVERTING FRAGMENT INTO HITS AND LEADS 6] OVERVIEW OF FBDD

3. FBDD >FRAGMENT BASED DRUG DESIGN ALSO KNOWN AS FRAGMENT BASED LEAD DISCOVERY. > THIS METHOD USED FOR FINDING LEAD COMPUNDS AS PART OF DRUG DISCOVERY. >FRAGMENTS ARE SMALL ORGANIC MOLECULES WHICH ARE SMALL IN SIZE AND LOW IN M.W . COMPARE TO THERE WHOLE MOLECULE COMPUND. >FBDD IS BASED ON IDENTIFYNG SAMLL CHEMICAL FRAGMENT ,WHICH MAY BIND ONLY WEAKLY TO THE RECPTOR AND THE GROWING THEM OR COMBINING THEM TO PRODUCE A LEAD WITH HIGHER AFFINTY. HTS FBDD >FRAGMENTS HITS ARE TYPICALLY HIGHLY “ LIGAND EFFICIENT ” POSSESS A HIGH BINDING AFFINTY PER HEAVY ATOM THUS ARE IDEAL FOR OPTIMIZATION INTO CLINICAL CANDIDATES WITH GOOD DRUG LIKE PROPERTY.

4. FRAGMENT DEFINATION >FRAGMENTS ARE DEFINED AS LOW M.W ., MODERSTELY LIPOPHILIC , HIGHLY SOULBLE ORGANIC MOLECULES > FRAGMENTS TYPICALLY BIND TO THEIR PROTEIN WITH LOW AFFINITY , GENRALLY IN THE µ,m to mM range, AND CAN BE GROW, MERGED, LINKED WITH ANOTHER FRAGMENT TO IMPROVE POTENCY.

5. RULES > IN ANALOGY TO LIPINSKI’S “RULE OF FIVE” A “RULE OF THREE” WAS PROPOSED TO DEFINE FRAGMENTS. > MAINLY “RULE OF FIVE” USE FOR LEAD MOLECULE AND” RULE OF THREE” USE FOR FRAGMENT MOLECULES “RULE OF FIVE” OR LIPINSKI RULE >LIPINSKI rule of 5 helps in distinguishing b\w drug like and non drug like molecules. >It predictes high probability of success or failure due to drug likness for molecules complying with2 or more rules.

6. RULES │ LIPINSKI RULES 1] M. MASS LESS THAN 500 DALTONS. 2] LOG P LESS THAN 5. 3] LESS THAN 5 H BOND DONER. LESS THAN 10 H BOND ACCEPTORS 4] ROTATORY BOND LESS THAN 10. 5]POLAR SURFACE AREA LESS THAN 140A.

7. RULES RULE OF THREE >RULE OF THREE STATES THT FRAGMENT SHOULD HAVE 1] A M.W. LESS THSN 300 DA. 2] CLOG P LESS THAN 3. 3] NO. OF H BOND DONORS <3 AND H BOND ACCEPTOR<3 >ADDITIONAL FILTER GIVES MORE DESIRABLE FRAGMENT LIKE COMPUNDS 1] NO. OF ROTABLE BOND <3 2] PSA <60A2

8. LEAD EFFICIENCY >FRAGMENT GENRALLY HAVE TYPICALLY AFFINITY NEED RO BE OPTIMIZED BY ADDING NEW FUNCTIONAL GROUP OR BY LINKING TWO HIT FRAGMENT BOUND IN ADJACENT POCKET. >LEAD EFFICIENCY IS A WIDELY USED CONCEPT AND IS GENRALLY USED FOR COMPARING DIFFENT HIT FRAGMENT TO GUID THE LEAD GENRATION AND OPTIMIZATION PROCESS. >LEAD EFFICINCY IS THE FREE ENERGY OF BINDING DIVIDED THE NUMBER OF HEAVY ATOM AND IS DEFINE BY EQUATION Δ G IS THE BINDING FREE ENERGY, R IS GAS CONSTANT, T IS ABSOLUTE TEMP. Kd is dissociation binding constant, IC50 ISCONC. OF INHIBITION REQUEIRD TO INHIBIT 50%ACTIVITY OF THE ENZYME. HAC IS NO. OF HEAVY ATOM. > A FRAGEMENT WITH A HIGH LE IS PREFERRD FOR OPTIMIZATION B/C , IT PROVIDES AN OPPORTUNITY TO OBTAIN HIGH ACTIVE COMPOUND WITH OUT INCREASING THE M.W. TOO MUCH.

9. CONVERTING FRAGMENT INTO HITS AND LEADS > OPTIMIZATION OF FRAGMENT TO OBTAIN POTENTIAL CLINICAL CANDIDATES > THREE BROAD STRATEGIES FOR COVERTING FRAGMENTS INTO HITS AND LEADS: 1] FRAGMENT growing 2] FRAGMENT MERGING 3] OR LINKING

10. FRAGMENT GROWING >This is the most frequent method of increasing potency for a fragment and a number of successful fragment campaigns have been carried out using this strategy. >Typically a single fragment in a binding pocket is 'grown' using chemical synthesis to pick up further interactions with the protein. >This is the case that is the most likely to arise where a single fragment binds to protein or multiple fragments bind to as pecific area of the binding pocket. >Structural information on how the ligand binds to the protein is key to guiding fragment development

11. FRAGMENT MERGING >This is where a number of fragments bind to a protein and bind in a similar region. > Using structural information the overlap of the fragments can be combined using chemical synthesis to increase the potency. >This is the case that is the most likely to arise where there is a common scaffold with variation on the substitution pattern is observed > Structural information on how the ligand binds to the protein is key to guiding fragment development

12. FRAGMENT LINKING >This is where a number of fragments bind to a protein and in different regions of the binding pockets or on the surface of a protein >Using structural information the fragments can be linked using chemical synthesis to increase the potency. >This is the most difficult approach to increasing potency as there has to be an optimal linker as well as ensuring the binding interactions of the fragments are maintained >Only a handful of sucessfull examples in the literature especially against protein-protein interaction targets

13. OVERVIEW OF FBDD

14. THANK-YOU