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Dr. Heba Abd ElRasheed Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy Cairo University 1 Drug- Receptor Interaction ● Drug: Compound reacting with biological systems (receptors) producing biological response. ● Receptors: are membrane bounded proteins that • selectively bind small molecules known as ligands that give some physiological response. ● Receptors: Protein molecules found on rigid or • semi-rigid biologically important macromolecules as: 1- Nucleic acids [DNA, RNA]. • 2- Cell membrane. 3- Enzymes [Acetyl choline esterase, MAO, ACE….]. • 4-………etc ●The biological activity of a drug is related to its affinity for the receptor. (the stability of drug-receptor complex) This stability is commonly measured by how difficult it is for the complex to dissociate, which is measured by its Kd the dissociation constant for the drug receptor complex at equilibrium: Kd = [drug] [receptor] / [drug-receptor complex]. The smaller Kd, the larger the conc of the drug-receptor complex. Drug + Receptor K on K off Drug-Receptor complex A drug becomes inactive as soon as its concentration in the extracellular fluids decreases. Therapeutic aspects of drug action Structurally Specific Drugs [SSD] Structurally Non Specific Drugs [SNSD] Drugs producing their effects by interaction with specific receptors. Their activity depends on 3D chemical structure of the drug which should adapt to the 3D structure of the receptor. Drugs producing their effects by physical phenomenon with no interaction with specific receptors. Biological activity depends on their physical properties E.g. Antacids, Adsorbents, General anesthetics. How does the Receptor perceive the ligand? Types of Drug-Receptor Interactions Reversible weak bonds Irreversible weak bonds 1. Ionic (electrostatic) 1. Covalent bonds: bonds. Acylation Phophorylation 2. Hydrogen bonds. Alkylation 3. Van der Waals interactions. 4. Dipole–Dipole bonds. 5. Ion-dipole bonds. 6. Hydrophobic interactions. 7.Charge transfer Weak interactions are possible only when molecular surfaces are close and complementary (bond strength is distance dependent). In general, the bonds formed between a drug and receptor are weak noncovalent interaction, so the effects produced are reversible Often it is desirable for the drug effect to last only a limited time so that its action can be terminated e.g. CNS stimulant. However, the effect produced by a drug may be persistent and irreversible as in case of chemotherapeutic agents as anti-cancer. 1] Covalent bond It is the strongest bonding force [250 Kj / mol]. It is preferred when long lasting irreversible effects are desired. E.g. Anti-bacterial (Chemotherapeutic agents) & Anti-cancer drugs. The drug effect is terminated through: 1- Catalytic cleavage of D-R linkage [by enzymes or acid-base catalysis]. 2- Metabolic turnover of receptor molecules. 1] Covalent bond E.g. Mechlorethamine [alkylating agent], through its Aziridinium moiety form covalent bond with SH; COO or PO4 anions of proteins or nucleic acids prevent their normal participation in cell division. 1] Covalent bond Example: alkylation of 7-position on guanine base in each of double strands of DNA CROSS LINKAGE. R 1 HN H2N 2 O 6 O HN H2N 5 .. N 7 8 3 O Nucleophilic site 4 + N 9 DNA Srand A R N CH2 CH2 Cl CH2 CH2 Cl HN H2N N CH2 CH2 N CH2 CH2 N N N N DNA Srand A O N NH2 DNA Srand B Cross-linked Product + N N DNA Srand B Guanine residue in DNA NH 2] Ionic bonds: For protein receptors at physiologic pH (7.4) Most drugs are either weak acids or weak bases in physiological pH It reacts with protein receptor through Basic group (+ve charge: cationic sites) e.g. guanidine group of arginine, imidazole group of histidine, NH2 of lysine. Acidic groups (-ve charge: anionic sites) e.g. COOH of aspartate and glutamate. Ionic interaction can be: [1] effective at distance farther than required for other types of interactions. [2] can persist longer. 2] Ionic bonds: The carboxylate group of the antidepressant Pivagabine forms an ionic bond with the guanidino group of arginine residue. O Pivagabine O H N 3 NH NH O H N 2 3] Hydrogen bonding It is a type of dipole-dipole interaction formed between electronegative atoms as O,N,…. & protons attached to electronegative atoms as NH2 or OH or COOH or carbonyl. X H Hydrogen donor: Carrying H atom. e.g. – OH , -COOH, NH , SH Y Hydrogen acceptor : Electronegative Heteroatom carrying lone pair of electrons. e.g. – O , -COO , N, S, Cl 3] Hydrogen bonding Types of H- bonds : a) Intramolecular: Strong within the same molecule. b) Intermolecular: Weak between different molecules. * H- bond may highly affect the activity of drugs O e.g. Methyl salicylate O C OMe C OMe H O OH o-Methylsalicylate with H-bond { unavailable free OH gp.} Active antirheumatic & inactive as antibacterial p-Methylsalicylate without H-bond { Available free OH gp.} Active antibacterial & inactive as antirheumatic Ionic bonds Hydrogen bonds 20 Kj / mol. Strong electrostatic bonding force between groups having opposite charges. Most drugs are weak acids or weak bases, when ionized in water react with the opposite charge on the receptor: * Cationic e.g. NH2 gp of amino acids. 40 Kj / mol. Formed between electro-negative atoms as O,N,Cl…. & protons attached to electronegative atoms. Hydrogen bonds easily brocken dissociation of D-R complex. It's formed between H-donor & H- acceptor: * CH3 group not donor not acceptor. * Anionic e.g. terminal COOH gp of * OCH3, F amino acids. * OH, NH2 H-donor & H-acceptor. H-acceptor. H Asp COO - +H 3N Lys Ser H 2C O H O CH2 Ser 4] Dipole-dipole & iondipole interactions Due to difference in electronegativity of certain atoms [e.g. O, N..] there's asymmetric distribution of electrons which makes an Electronic Dipole (Permanent polarization) C O C S C Cl O,N,S & Cl are C N O carbonyl Electronegative atoms OR O ester NH2 O amide C cyanide N 4] Dipole-dipole & iondipole interactions This dipole can form weak bond with regions of high or low electron density such as other dipoles or ions Ion-Dipole interaction Dipole –Dipole interaction ● It is an electrostatic ●It is an electrostatic attraction between a full attraction between partial opposite charges. charge [ion] and a partial charge [dipole]. Because the charge of a dipole is less than that of ion so dipole-dipole interaction is weaker than ion-dipole 4] Dipole-dipole & iondipole interactions N C N Hypnotic agent Zaleplon O ion-dipole O O H N Zaleplon N O N dipole-dipole 5]Charge Transfer Interactions Interaction between electron deficient “electron acceptor” and electron rich moiety “electron donor”. The charge transfer complex is a molecular dipole-dipole interaction. Electron donor groups Electron acceptor groups ● gps contain π-electrons such as alkenes, alkynes and aromatic moieties with electron-donating substituents or gps that contain a pair of nonbonded electrons such as O, N and S. ●● Electron donor [aromatic ring of tyrosine or the carboxylate gp of aspartate]. ● gps contain electron deficient π-orbitals such as alkenes, alkynes and aromatic moieties with electron-withdrawing substituent's and weakly acidic protons. ●● Electron acceptor [cysteine]. ●●● Electron donor and acceptor [histadine, tryptophan and aspargine]. 5]Charge Transfer Interactions 2) The fungicide chlorothalonil & the tyrosine ring of the receptor CN CN Cl Cl Cl Cl Cl Cl CN CN Cl Cl chlorothalonil Electron defficient drug OH OH Tyrosine moiety ( Electron rich receptor ) 6]Hydrophobic Interactions (lipid–lipid interaction) In the presence of a nonpolar molecule or region of a molecule, the surrounding water molecules orient themselves and, therefore, are in a higher energy state than when only other water molecules are around. When two nonpolar groups, such as a lipophilic group on a drug and a nonpolar receptor group, each surrounded by ordered water molecules, approach each other, these water molecules become disordered in an attempt to associate with each other. 6]Hydrophobic Interactions (lipid–lipid interaction) •This increase in entropy, therefore, results in a decreased in the free energy that stabilizes the drug-receptor complex. •This stabilization is known as a hydrophobic interaction. •The topical anaesthic butamben is described in a hypothetical hydrophobic interaction with an isoleucine group. 6]Hydrophobic Interactions (lipid–lipid interaction) e.g. : Butamben (Local anaesthetic) hydrophobic interaction with isoleucine group of the receptor O H2O H2N O H2N O Butamben O Isoleucine 7] Van der Waals interactions Formed between hydrophobic molecules [either aromatic or aliphatic] due to the difference in electron density. Molecules of high electron density attract area of low electron density on other molecule (Temporary dipole). It's due to difference in electron density in these neutral, non-polar molecules a transient area of e-density & another area of edensity the area of e-density on one molecule attracts another hydrophilic area of e-density on another molecule. It is inversely proportional to distance. Drug Van der waal interaction E 1 d Receptor Factors affecting DrugReceptor interactions A) Hydrophobicity (= lipophilicity) It affects drug absorption, metabolism, binding with receptor & its penetration to brain. e.g. Barbiturate & Thiobarbiturate B) Ionization Drugs undergo ionization according to their pKa values Unionized drug is non polar (lipophilic) & the ionized one is polar (hydrophilic). C) Steric factor N COOH O SH 1st Generation: Captopril [Capoten®] CH3 •Disadvantages: (1) Due to SH group Rash and loss of taste. (2) It is rapidly inactivated by formation of disulfide bridge short acting. 2nd Generation [with COOH group Dicarboxylate] e.g. Enalapril [Ezapril® ] 3rd Generation [with phsophinate] e.g. Fosinopril [Monopril®] ACE (angiotensin converting enzyme) & ACEI Glutamate [protonated] Zn++ H (+) binding to Zn++ hydrophobic bond H-bond (-) ACE [ metallo protein enzyme ] Drug ionic Concept of structure-based drug design: •So, the requirements for the ACE inhibitor drug is : (1) Contain anionic site [COO-] (2) Contain H-bond forming group [C=O] (3) Contain SH, COO- or phosphinate group to react with Zn++. (4) Contain hydrophobic moiety [if methyl as in captopril S isomer is more active > R] How does a receptor change its shape? •Hypothetical receptor may be a part of an ion channel that is closed when neurotransmitter is absent. •When drug bind hypothetical receptor receptor alters its shape to obtain the best binding interaction [conformational changes]. •Bonding forces between drug & receptor must be large enough to change the shape of receptor BUT not so strong to make the messenger be able to leave again. •COO- group of the receptor is pulled closer to + ve nitrogen of the messenger opening of lock-gate. •Gate remains open till the messenger detaches from the binding site. •Finally, the receptor returns to its original shape. O H O H H - O OOC NH2Me H O H H - OOC NH2Me