Rational design of enzyme inhibitors (1).pptx

RATIONAL DESIGN OF ENZYME INHIBITION

1. Rational design of enzyme inhibitors… Presented by , Shoaib ( suvaiv )- 1600100395 Faculty of pharmacy ,integral university L ucknow

2. Rational design for covalent enzyme inhibitors… Rational design : design to fit known structurally identified biological site . Rational design of enzyme inhibitors : when the structure of a enzyme binding site is known then based on these design of inhibitors can be done . - design is based on the- number of positive ionisable groups , aromatic rings, hydrogen bond acceptor, hydrogen bond donor , through which substrate showed interaction at the active site .

3. Example - this is an example of the known sites of ACE and binding of captopril to ACE

4. Rational design for covalent enzyme inhibitors… Covalent binding : binding of inhibitors with enzyme’s active site with forming a covalent bond . Covalent bond – mutual sharing of electron between two atom .it forms between atoms of same elecreonegativity or slight defference in their electronegativity . Polor covalent bonding – forms between the atoms having small defference in their electronegativity such as HCl , HO and so on .

5. NonPolor covant bonding – forms between the atoms of same electronegativity such as H 2 , Cl 2 , O 2 and so on . Covalent bonding is an irriversible bonding , bond strength can range from 40-140 Kcal. These bonds are difficult to break and so are termed irriversible .

6. Approaches for rational design of covalently binding enzyme inhibitors Affinity label Mechanism based inhibitors Pseudoirreversible inhibitors

7. 2 Pseudoirreversible lnhibitors : They have some features in common with both affinity labels and mechanism-based inhibitors . Example - Acetylcholinesterase ( AcChE ) rapidly breaks down acetylcholine, thereby lowering its concentration in the synaptic cleft and ensuring that nerve impulses are of a finit Length . a nucleophilic serine residue reacts with the substrate to form an acetyl-serine intermediate (100) with concomitant release of choline . This intermediate is then rapidly hydrolyzed by water producing acetate and regenerated enzyme .

8. Eg – irriversible inhibition : acetylcholinesterase decreases the conc.in synaptic cleft

9. Agents such as parathion (101) and sarin (102) have found utility as because they react with the enzyme to form the active-site serine-phosphate esters, (103) and (104). These esters are hydrolyzed extremely slowly by water, making the inhibition effectively irreversible.

10. Example of PLP-dependent enzyme GABA – T (y- Aminobutyric acid transaminase )-the enzyme responsible for the breakdown of GABA. GABA-T is a PLP-dependent enzyme and a wide variety of mechanism-based inhibitors have been described for this enzyme. Vigabatrin (8), currently used as an antiepileptic drug, provides an excellent example of this approach.

11. Mechanism of inhibition As with the normal mechanism of the enzyme, the inactivation starts with Schiff base formation with the enzyme-bound pyridoxal phosphate , followed by removal of an a-proton by an active-site base to form the reactive electrophilic intermediate (82 ). This then partitions between hydrolysis of the Schiff base linkage , resulting in the keto product (83) and enzyme reactivation, and Michael-type addition of an enzyme active-site nucleophile , resulting in a stable covalently bonded enzyme adduct (84).