L3-Chemical_Bonds PDF

Review L2 Acid Functional Groups Carboxylic Dicarbonyl Sulfonamide Sulfonylurea Tetrazole Phenol 2.5-5 4.5-8.5 4.5-11 5-6 4.5-6 9-10 Thiol Phosphate...

Review L2 Acid Functional Groups Carboxylic Dicarbonyl Sulfonamide Sulfonylurea Tetrazole Phenol 2.5-5 4.5-8.5 4.5-11 5-6 4.5-6 9-10 Thiol Phosphate Phosphonate Sulfate 10-11 1.5-2.5/6.5-7.5 1.5-2.5/6.5-7.5 1-2 Adjacent Groups (R, R1, R2) Acidity pKa Electron-Withdrawing functional groups Functional groups that can delocalize electrons, such as benzene ring  Review L2 Base Functional Groups Aliphatic Amine Aromatic Amine imine hydrazine Amidine Guanidine 9–11 2-5 3-5 (7-8 if R1 7.5-8.5 10-11 12-13 and R2 are aliphatic) Heterocycles: 1-5 Adjacent Groups (R, R1, R2) Basicity pKa of the conjugated acid Electron-donating functional groups Functional groups that increase steric hindrance  Homework Question: Each of the drug molecules below contains at least one ionizable functional group. Determine whether the drug molecule is acidic, basic, or amphoteric in character. Haloperidol Basic Dyclonine Basic Acidic Naproxen Acidic Diaplasinin  Homework-Continued Question: Determine if there are any ionizable functional groups and then fill in the table. Drug Acidic Basic Functional Functional Groups Groups Repaglinide Carboxylic acid Aniline Repaglinide Gliclazide Gliclazide Sulfonylurea Tertiary amine Ciprofloxacin Carboxylic acid Tertiary amine Aniline Irbesartan Tetrazole Imine Ciprofloxacin Irbesartan Topic 3: Chemical Bonds Junmei Wang Ph.D. Associate Professor Department of Pharmaceutical Sciences School of Pharmacy Tel: 412-383-3268 Email: [email protected]  Learning Objectives 1. Explain the differences between covalent bonds and noncovalent bonds. 2. Identify the major types of covalent bonds and explain both the beneficial and detrimental effects that these types of bonds can have on the activity of drug molecules. 3. Explain why each type of noncovalent bond has a unique distance requirement and bond energy. 4. Analyze a drug molecule and identify the types of bonds that can be formed by each of its functional groups. 5. Investigate drug-receptor interactions using a toolkit like the “ligand interaction” function provided by RCSB Protein Data Bank (www.rcsb.org). 6  Basic Concepts on Covalent Bonds The strongest bond that can be made between a drug molecule and its biological target. The overall strength is in the range of 40-150 kcal/mol. The formation of covalent bond is generally considered irreversible. In most cases, normal metabolic turnover of enzymes and receptors and the cellular replenishment are the only way to reverse the inactivated enzymes or proteins. Advantages of using covalent bonds 1. Sometimes more effective than noncovalently bound drugs 2. Selective, low-dose Disadvantages of using covalent bonds 1. The formation of covalent bond is irreversible 2. Prolonged drug action 3. High demanding on drug specificity 7  Examples of Covalent Bonds 1. Anticancer drugs and DNA 2. Insecticides and an enzyme (acetylcholinesterase) 3. Penicillin and bacterial cell walls 4. Proton pump inhibitors and gastric acid secretory pump Aspirin Chlorambucil Cefoxitin Clopidogrel Anticancer, an Anti-inflammatory, A -lactam Antithrombotic alkylating agent antithrombotic antibiotic 8  Specific Types of Covalent Bonds Alkylation Occurs when a nucleophilic atom or functional group present on receptor attacks a highly electrophilic atom or functional group on the drug molecule. Nucleophile Aziridinium Nuc-Macromolecule Electrophile Chlorambucil 9  Specific Types of Covalent Bonds Acylation Occurs when a nucleophilic atom or functional group present on receptor attacks an ester, lactone, amide, lactam, or carbamate. Aspirin + Salicylic Acid Cyclooxygenase (COX) Phosphorylation 10 Rearrangement Reactions  Specific Types of Covalent Bonds Phosphorylation The procedure of forming organophosphate. It plays an important role in aging. Take the irreversible inhibition of acetylcholinesterase by Isoflurophate as an example: hydrolysis phosphorylation 11 Rearrangement Reactions  Basic Concepts on Noncovalent Bonds 1. Most drugs bonds to their biological targets through the formation of noncovalent bonds 2. The strengths of noncovalent bonds rang from 0.5 to 10 kcal/mol. 3. The overall binding strength is the summation of all of the individual noncovalent interactions. 4. The formation of a noncovalent bond is reversible 5. The ability of any single noncovalent bond to form is inversely proportional to the distance between the functional group present on the drug molecule and a complementary functional group present on the biological target. 6. Steric factors and the stereochemistry of drug molecules are also very important for the interactions between a drug and its biological target. 12 Comparison Between Covalent and Noncovalent Bonds Covalent Bonds Noncovalent Bonds Occurrence in drug Low High molecules Bond Strength 40-150 kcal/mol 0.5 to 10 kcal/mol Formation reversible Typically, No Yes Duration of drug action Prolonged Normal Binding specificity High Normal requirement 13  Ionic Bonds Occurs between ionized acidic and basic functional groups or ionized acidic and quaternary ammonium functional groups. Bond strength ranges from 5-10 kcal/mol Bond strength is proportional to 1/r, where r is the distance between the ionized functional groups. COX Ibuprofen Salicylic Acid interacts with Arg419 of Arabidopsis NPR Protein (PDB 6WPG) 3D View: 6WPG (rcsb.org) 14  Charged Amino Acids Acidic Functional Groups Basic Functional Groups C-terminus N-terminus Aspartic Glutamic Histidine Acid 𝑝𝐾𝑎 = 12.5 Acid Lysine 𝑝𝐾𝑎 = 6.0 𝑝𝐾𝑎 = 3.6 𝑝𝐾𝑎 = 4.2 𝑝𝐾𝑎 = 10.5 Arginine 15  Dipole Interactions Dipole interactions occur between functional groups in which there is a partial charge separation between the atoms involved in the individual bonds of the functional group. Electronegativity determines the direction and amount of the partial separation of the charge. Atom Electronegativity Value Atom Electronegativity Value F 3.98 I 2.66 O 3.44 S 2.58 Cl 3.16 C 2.55 N 3.04 H 2.20 Br 2.96 P 2.19 16  Dipole Formation O and N are more electronegative than C and H - + - + - - + + The electronegativity values of C and H are similar to one another. As such, no significant dipole in a C-H bond. The electronegativity values of S and H are similar to one another. For S-H bond, S bears partial negative charge due to its larger size. The electronegativity value of P is much smaller than O, thus, O bears partial negative charge in P-O bond All halogen atoms (F, Cl, Br and I) are more electronegative than C. 17  Dipole Interactions Type Bond Strength Examples Three types Ion- 1 + ∝ Dipole 𝑟2 - Chlorpheniramine Explore dipole interactions using graphics tools from Dipole- 1 - + www.rcsb.org ∝ 3 + Dipole 𝑟 - Ezetimibe 3D View: 4DKL (rcsb.org) H-Bond 1 ∝ 𝑟3 - + - Morphine + 18  Hydrogen Bonds H-bond is a specialized type of dipole-dipole interaction with bond strength ranging from 3 to 7 kcal/mol. - + - o X: H-bond donor o Y: H-bond acceptor H-bond formation conditions o Distance between H and Y: 1.6 to 2.0 Å o  X-H-Y angle: 120 – 180 degrees o Strongest H-Bond occur when X-H…Y is colinear and O is a better H-bond donor than N, while N is a better H-bond acceptor than O, thus the H-Bond strengths follows this trend: O-H … N > O-H … O > N-H … N  N-H … O 19  Hydrogen Bonds H-Bond Donors Thiol H-Bond Acceptors Heterocyclic Nitrogen Ketone Ester Ether Heterocyclic Disubstituted Disubstituted Fluorine Nitrogen carbamate H-Bond Donors and Acceptors amide Hydroxyl Phenol Amide Primary and Carboxylic Carbamate Urea secondary acid unionized 20 amines  Advantage of Hydrogen Bonds 1. Hydrogen bonds are generally stronger than other types of dipole-dipole interactions. 2. Hydrogen bonds can enhance the strength of an ionic bond. 3. Hydrogen bonds are important for enhancing the water solubility of a drug molecule. 4. Intramolecular hydrogen bonds can be important for determining the preferred conformation for a drug molecule or a biological macromolecule. 3D View: 1IKV (rcsb.org) 21  van der Waals (VDW) Interactions Three types of forces: Type Distance Bond Dependence Strength 1. Keesom: dipole-dipole 2. Debye: dipole-induced dipole Covalent Complex Strongest 3. London dispersion: induced Ionic interaction 1 Very strong ∝ dipole – induced dipole 𝑟 VDW typically refers to Debye Ion-Dipole 1 Strong ∝ 2 and London dispersion forces, 𝑟 Dipole-Dipole 1 Moderate with bond strengths ranging ∝ 3 𝑟 from 0.5 to 1.0 kcal/mol. Ion-induced dipole 1 Weak Some functional groups, such ∝ 4 𝑟 as alkyl chains and aromatic Dipole-induced dipole 1 Very Weak rings can form multiple VDW ∝ 6 𝑟 interactions, and the total bond Induced dipole-induced 1 Weakest ∝ 6 strength can be substantial. dipole 𝑟 22  Hydrophobic Bonding hydrophobic effects refers to the tendency of lipid-soluble, or hydrophobic, molecules to interact with one another in an aqueous, or hydrophilic, environment. In terms of drug binding interactions, a hydrophobic effect (or a hydrophobic interaction) is not directly related to bond formation, but rather to the gain in entropy that occurs when two hydrophobic functional groups are attracted to one another. 23  Pi-Pi Interactions (-Stacking) 3.35Å 3.5Å 3.8Å Sandwich Parallel-displaced T-shaped 24  Chelation and Complexation Chelation is a process that occurs whenever two distinct electron donating groups, present on the same molecule, bind to a metal ion and form a ring structure. Ethylenediaminetetraacetic acid (EDTA) can chelate many metal ions (Pb2+, Hg2+, Ca2+, Fe2+, etc.) Pb2+ Pb2+ The chelation of tetracycline with Magnesium 3D View: 4B3A (rcsb.org) Tetracycline Mg2+ The complexation of Captopril with zinc ion Zn2+ 25  Drug-Receptor Interactions Receptor (R): macromolecules with complex structures, located on cell membranes or intracellularly which, when activated, trigger a specific physiological response ❖ Common drug targets: membrane receptor proteins (GPCRs), ion channel proteins, enzymes (protease and kinase), transporters Ligand (D): Ion or molecule that binds to receptor and forms a complex Drug-Target Complex 𝐷+𝑅 𝐷𝑅 ⟶ 𝐷𝑟𝑢𝑔 𝐸𝑓𝑓𝑒𝑐𝑡 1. Affinity (first reaction): measures the drug’s ability to form a drug/receptor complex (DR) 2. Efficacy (second reaction): describes intracellular events that occur subsequent to DR formation 3. Drugs may be agonists or antagonists ❖ Agonists bind to the receptor and initiate a response ❖ Antagonists bind to the receptor but produce no effect (thereby reducing or antagonizing the natural agonist effect) 26  Factors Affecting Drug-Receptor Interactions Drug-target binding involves multiple types of bonds, such as covalent, ionic bonds, van der Waals and hydrogen-bonds, and hydrophobic interaction. 1. Weaker bond types are the most common 2. The electrostatic attraction of the ionic bond may be the initial force that draws a drug to its receptor 3. The initial association is then reinforced by weaker van der Waals forces, hydrogen bonds and hydrophobic interactions 4. The in vivo activity of a drug is also affected by physicochemical and pharmacokinetic factors 27  Plasma Protein Binding Plasma proteins that bind drug molecules is an example that a drug interacts with a macromolecule that does not produce a therapeutic response. 1. Albumin: weak acids (high affinity, the ionized form is the primary form that bind to albumin), weak bases, nonelectrolytes 2. Alpha-1 acid glycoprotein (AGP): weak bases Drug binding is freely reversible: 1. Involves the same kind of chemical bonds responsible for drug-receptor interactions 2. Binding is usually relatively nonselective – nonspecific binding Drugs bound to plasma proteins may not cross biological membranes 1. Drugs must first dissociate to its “free”, nonprotein-bound form 2. Serves as a drug reservoir in the plasma Drugs may compete with each other for binding to plasma proteins ❖ A potential source of drug interactions 28  In Class Practice -1 I: ionic interaction ID: ion-dipole DD: dipole-dipole 2 3 4 HB: hydrogen bond 1 Venetoclax V: van der Waals H: hydrophobic P: pi-pi stacking IP: ion-pi interaction C: chelation For each boxed functional group: 1. Identify all possible drug binding interactions. Assume that these drug interactions are occurring at a physiological pH of 7.4. 2. Based on the functional groups present within the structure of Venetoclax, is it possible for this drug to form ionic bonds with its biological target? Why or why not? 29  1 I: ionic interaction In Class Practice -2 ID: ion-dipole DD: dipole-dipole For each boxed functional group: HB: hydrogen bond 1. Identify two possible drug binding V: van der Waals interactions with an amino acid side chain as H: hydrophobic shown above P: pi-pi stacking 2. Identify two possible drug binding IP: ion-pi interaction interactions with an amino acid side chain in C: chelation an environment pH=7.4). 3. Which functional groups (1–4) can participate in the following types of interactions (at pH = 7.4)? 4 A: Cation-π (as Pi system) 3 B: Ionic C: Chelation 2 D: van der Waals E: Ion-dipole (as the dipole) Elamipretide 30  Homework Arformoterol is a β2 receptor agonist that is a long-acting bronchodilator. Evaluate the structure to determine what type of interactions might be possible between this drug molecule and its biological target at pH of 7.4. Functional Group Acid/Base Nature Ionized or Not H-Bond types (Acceptor, Donor, Both, or neither) Amide Neutral Phenol Acidic Secondary Alcohol Neutral Secondary Amine Basic Ether Neutral 31