Drug Receptor Binding Forces

Different types of binding forces and interactions in drug receptor complex

1. DRUG RECEPTOR INTERACTIONS. By Tathagata Pradhan M. Pharma (P’ Ceutical Chemistry) 1 st Sem

2. INTRODUCTION Drugs : The WHO (1966) defined it as – “Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.” All drugs are chemicals but not all chemicals are drugs. The ability to bind to a receptor is mediated by the chemical structure of the drugs that allows it to interact complementary surfaces on the receptor. Once bound to the receptor agonist activates or enhances cellular activity. Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force of myocardia contraction or drugs that bind to alpha receptors on blood vessels to increase blood pressure.

3. RECEPTORS: A receptor is the specific chemical constituent of the cell with which a drug interacts to produce it’s pharmacological effects. Some receptor sites have been identified with specific parts of proteins and nucleic acids. The term drug receptor or drug target denotes the cellular macromolecule macromolecular complex with which the drug interacts to elicit a cellular response, i.e., a change in cell function. D+ R D-R Drug Response

4. RECEPTORS: A Receptor is analogous to a switch that it has two configurations : ‘’ON’’ and ‘’OFF’’ Four Primary Receptor Families Ligand gated Ion Channel G-protein coupled Receptor Systems Enzyme-linked receptors Intracellular receptors

5. DRUG RECEPTOR INTERACTIONS Further Terminology – Affinity: the strength (Avidity) of drug binding to receptor. Efficacy/intrinsic activity: the ability of the drug to induce a response in the receptor post-binding (i.e. through a conformational change in the receptor). Potency: the powerfulness of a drug, depending on its affinity and efficacy. Full agonist: an agonist which has the ability to induce a max response in tissue post-binding.

6. DRUG RECEPTOR INTERACTIONS Partial agonist: an agonist which can only produce a partial response in tissue ,and in conjunction with a full agonist may act with antagonistic activity. Selectivity: the preference of a drug for a receptor (this is not specificity; specific suggests one drug one receptor. In fact the adverse effects of many drugs are caused by the binding to their non-preferred receptors).

7. DRUG RECEPTOR INTERACTIONS Structure-activity relationship: referring to the fact that the activity of drug is closely related to the structure of the drug. therefore small changes in the structure may produce large effects on its action. This is like the lock + Key theory, and is useful in drug design: small changes to an agonist may in turn form an antagonists, as well as altering the pharmacokinetics of the drug. Receptor reserve refers to the fact that in many tissues, not all receptors need to be occupied in order to achieve the maximal tissue response With regards to physiological tissue, this results in an increased sensitive + speed of response.

8. DRUG RECEPTOR INTERACTION Includes-

9. IMPORTANT INTERACTIONS (FORCES) INVOLVED IN THE DRUG RECEPTOR COMPLEX Interactions involved in the drug-receptor complex are the same forces experienced by all interacting organic molecules. these include: Covalent bonding Ionic (electrostatic) interactions Ion-dipole and dipole-dipole interactions Hydrogen bonding Charge-transfer interactions Hydrophobic interactions Van der Waals interaction

10. 1. Covalent Bonds The covalent bond is the strongest bond, generally formed by sharing of electrons between two atoms. It is formed by a drug receptor interaction, except with enzymes and DNA. The majority of drugs combine with their receptor by weak molecular interactions. These interactions forms a strong link between the drug and its receptor but individually the interactions are reversible. The covalent bonds are important as compare to other bonds.

11. The compounds carry reactive groups capable of forming covalent bonds, the substrate may be irreversibly bound to the drug-receptor complex by covalent bond formation with reactive groups adjacent to the active site. The diuretic drug ethacrynic acid is an α,β-unsaturated ketone, thought to act by covalent bond formation with sulfhydryl groups of ion transport systems in the renal tubules. Another example of a drug that covalently binds to the receptor is selegiline, an inhibitor of monoamine oxidase-B .

12. Examples of covalent bonding 1.Organo-phosphate anti cholinesterases ( AChE’S ) These substances have been used as insecticides (e.g., malathion, parathion) and also as nerve gases in chemical warfare ( e.g . Tabun , Sarine) They produce irreversible inhibition of AChE by phosphorylating a serine hydroxyl at the active site.

13. 2. Penicillins Bactericidal effects involve irreversible inhibition of the transpeptidase(TP) mediating the cross-linking of bacterial cell wall units (needed for rigidification of the cell wall) The 4-membered B-lactam ring (required for antibacterial activity) is a structurally similar to (i.e., is “isosteric”) with the moiety involved in cross-linking (D-alanine) The B-lactam ring is highly strained and therefore chemically reactive.

14. The B-lactam ring readily opens (relieving the “strain”) and forms covalent bonds with the TP The structural analogy between the B-lactam ring and D-alanyl-D-alanine directs covalent bond formation to the serine at the active site of the TP causing enzyme inactivation, resulting in inhibition of cell wall strand cross-linking cell death

15. Penicillin is highly allergenic Opening of “strained” B-lactam ring covalent attachment to proteins allergic response to modified protein now recognized as “foreign” A variety of penicillin-derived haptenic determinants can form – and allergy to one penicillin may not necessarily indicate allergy to all – but best to assume allergy to one penicillin = allergy to all analogues

16. 3.Nitrogen mustards These B-halo-alkylamines are derivatives of nitrogen mustard are widely used as antineoplastic agents. Their mode of action involves the formation of a highly reactive ethyleneiminium ion The interaction with nucleophilic (electron-rich) groups involves covalent bond formation by alkylation

17. Bifunctionally produces cross-linking of adjacent strands of DNA –resulting in inhibition of cell proliferation The nature of R group in nitrogen mustard derivatives determines their therapeutic uses

18. The irreversible alpha-adrenoceptor blocker phenoxybenzamine (POB) is a B-halo-alkylamine and acts like the nitrogen mustards POB is used in the surgical management of phaeochromocytoma were tumor removal may cause the release large amounts of catecholamines

19. 2. Ionic (Electrostatic) Interactions For protein receptors at physiological pH (Ph 7.4 ), basic groups such as the amino side chains of arginine, lysine are protonated and therefore, provide a cationic environment. Acidic groups, such as the carboxylic acid side chains of aspartic acid and glutamic acid, are deprotonated to give anionic groups. Drug and receptor groups will be mutually attracted provided they have opposite charges. This ionic interaction can be effective at distances farther than those required for other types of interactions, and they can persist longer.

20. In biological systems, it happens between residues having carboxylate group such as aspartic acid & glutamic acid (acidic amino acids), and ammonium ions such as Histidine, Lysine and Arginine (basic amino acids).

21. Ionic interactions Ionic interactions are not usually primary determinants of binding specificity one exception is the selective antagonism of heparin by protamine (these are oppositely charged polymers) Ionizable moieties involved in pharmacologically revelant electrostatic interactions include ; carboxylate, amino, phosphate, imidazole and guanidinium group

22. Other pharmacologically relevant ion-ion interactions include the following: The quaternary N+ of acetylcholine with the anionic site of AChE The ionic interaction of the guanidinium groups of tetrodotoxin and saxitoxin at the outer surface of Na+ channels The cationic form of local anesthetics binds to the inner surface of Na+ channel

23. 3. Ion-Dipole and Dipole-Dipole Interactions As a result of the greater electronegativity of atoms such as oxygen, nitrogen, sulphur, and halogens relative to that carbon, C-X bonds in drugs and receptors, where X is an electronegative atom, will have an asymmetric distribution of electrons this produce electronic dipoles. These dipoles in a drug molecule can be attracted by ions (ion-dipole interaction) or by other dipoles (dipole-dipole interaction) in the receptor, provided charges of opposite sign are properly aligned. Because the charge of a dipole is less than that of an ion, a dipole-dipole interaction is weaker than an ion-dipole interaction.

24. Ion-dipole occur when ionic group on one molecule interacts with a permanent dipole on a second molecules. It is stronger than dipole-dipole interaction. (decreasing to the relative square of the separation).

25. 4. Hydrogen Bonds Hydrogen bond are a type of dipole-dipole interaction formed between the proton of a group X-H, where X is an electronegative atom, and one or more other electronegative atoms (Y) containing a pair of non-bonded electrons. The most significant hydrogen bonds occur in molecules where X and Y are N and O. X removes electron density from the hydrogen so it has a partial positive charge, which is strongly attracted to the non- bonded electrons of Y. The interaction is denoted as a dotted line, -X-H----Y— X is referred to as the hydrogen bond donor and Y is the hydrogen bond acceptor. When X and Y are equivalent in electronegativity and degree of ionization, the proton can be shared equally between the two groups, i.e. –X---H—Y-.

26. Hydrogen bonding shown by dotted line (X, Y = oxygen or nitrogen)

27. H-bonding Should have H-Bond acceptor (the electron rich atom, slightly negative) and H-Bond donor (electron-deficient hydrogen, slightly positive). Stability of this bond is -1 to -7 kcal/mol H-bonds are between 1.5-2.2 Å.

28. Increase electron density, better H-Bond acceptor, so anions are better than uncharged compounds e.g. carboxylate anion.

29. If the lone pair on nitrogen atom are delocalized, this will weaken the HBD capacity H-Bond donors are better if the H is more electron deficient by attachment to more electron deficient atom such as quaternary ammonium compounds.

30. Hydrogen bonding Of two types: Intramolecular H-bonding: which occur within the same molecule. Intermolecular H-bonding: occurs between two nearby molecules

31. H-bonding The occurrence of intramolecular H-bonding could affect the pharmacological action of a drug. P -hydroxybenzoate has more potent antibacterial action compared to methyl salicylate, it is normally used as food additive as preservative.

32. 5.Charge Transfer Complex Occurs between an electron donor group in one molecule and an electron acceptor in another. Electron donors such as alkenes, alkynes and aromatic ring bearing an electron donating group, and atoms having pairs of non-bonded electrons such as O, N and S Electron acceptors such as aromatic ring bearing an electron withdrawing group, These groups might exist in the receptor binding sites: Eg. - Electron donor such as tyrosine and carboxylates Electron acceptor such as cysteine Having both: such as Histidine, tryptophan and sparagine .

33. Charge-Transfer bonds

34. 6. Hydrophobic Interaction Hydrophobic interactions involve the displacement of ordered layers of water molecules which surround hydrophobic regions of molecules. The resulting increase in entropy contributes to the overall binding energy.

35. 7. Van der Waals or London Dispersion Forces Atoms in non polar molecules may have a temporary non-symmetrical distribution of electron density, which results in the generation of a temporary dipole. As atoms from different molecules (such as a drug and a receptor) approach each other, the temporary dipoles of one molecule induce opposite dipoles in the approaching molecule. Consequently, intermolecular attractions, known as van der Waals forces, result. These weak universal forces only become significant when there is a close surface contact of the atoms.

36. Van-der Waals forces Occurs due to temporary non-symmetrical distribution of electron density, this will form temporary dipole that will interact with nearby dipole. Stability accounts for only -0.5 kcal/mole, this means that this type of bonds are much weaker than other bonds.

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