med chem exam 1

drug

a chemical substance of known structure, other than an essential dietary ingredient, which when administered to a living organism produces a biological effect, usually an organic compound

drug targets

a molecule in the body that is intrinsically associated with a particular disease process and can be addressed by a drug to produce a desired therapeutic effect, proteins and nucleic acids

drug-target interactions

a drug (I) binds to its target (E) to form a drug-target complex, the drug target (E-I) complex changes the conformation of the target, the drug-target complex (E-I) has lower energy than the sum of a drug + a free target

covalent bonds

a chemical bond that involves the sharing of electron pairs between atoms, only a small number of drugs act by forming these bonds, the duration of action of this bond may be too long for a given therapeutic indication, lack of specificity and irreversible bonds could lead to prolonged adverse effects, may cause toxicity and specific handling because of high reactivity

four major covalent bonds with drugs

alkylation, acylation, phosphorylation, rearrangement

alkylation

covalent bond, a drug adds an alkyl group to its target, nitrogen mustard and chemotherapy (many side effects)

acylation

a drug adds an acyl group to its target, drug molecule contains ester, lactone, amide, or carbamate, target molecule presents a nucleophilic atom (N, S, O), aspirin acylates the Ser with an acetyl group at its target enzyme COX, beta-lactam antibiotics produce antibacterial activity through acylating their target enzyme, reversible

phosphorylation

a drug adds a phosphate group to its target, organophosphates, phosphorylate acetylcholinesterase irreversibly, very toxic and used as insecticides

rearrangement

usually occur during drug metabolization, active metabolite forms a covalent bond with a drug, majority of enzymes will add an OH group to the drug and double bonds will rearrange, hydrolysis occurs and COOH and SH forms, ends with disulfide bond

non-covalent bonds

most drugs bind to their target via these bonds, overall binding strength is a sum of all the individual non-covalent interactions, the binding strength is related to the overall affinity of a drug to its biological target, readily reversed

five major non-covalent bonds with drugs

ionic bonds (electrostatic interactions), dipole, Van der Waal’s (hydrogen bonds), additional aromatic

non-covalent bond drug strength

the strength of this bond is inversely proportional to the distance between the functional group on the drug and the complementary functional group on the biological target (closer = stronger)

ionic bonds (electrostatic interactions)

occurs between ionized acidic and basic functional groups or ionized acidic (-) and quaternary ammonium (+) functional groups, strongest among non-covalent bonds (20-40 kJ/mol), pKa of functional groups affects whether ionic bonds form at specific pH

dipole interactions

electrostatic forces of attraction, creates partial charge due to difference of electronegativity values of the atoms, dipoles refer to the separation of positive and negative charges (dipoles) within a system, greater difference of electronegativity = bigger dipole moment, 2-8 kJ/mol

hydrogen bonds

special dipole-dipole interaction between a partially positively charged hydrogen atom attached to a highly electronegative atom (F, O, N) and another partially negatively charged atom (F, O, N), 16-60 kJ/mol

van der Waals’ interaction

interaction between any atoms or molecules, caused by temporary dipoles due to uneven or unsymmetrical electronic distribution or induced dipole, very weak (2-4 kJ/mol), overall contribution can often be crucial to binding due to many such interactions, liquid nitrogen

additional aromatic interactions

pi-pi stacking and cation-pi stacking

pi-pi stacking

one aromatic group from the drug molecule, the other aromatic group from the target protein (Phe, Tyr, Trp)

cation-pi stacking

important binding force, cation group from drug molecule, aromatic group from the target protein (Phe, Tyr, Trp)

chelation

ions and molecules to metal ions, formation of a coordination compound in which metal ion is bound to a ligand at 2 or more points on the ligand, some drugs chelate with the Ca2+ and lose its activity, cannot be taken orally with calcium

story of aspirin

developed by Hoffmann at Bayer, willow leaves have similarity to aspirin

story of Qinghaosu artemisinin

treats malaria, qinghao plant

drugs from other natural sources

soil samples (bacteria and fungi), fungi, marine organisms

biologics (biological drugs)

made from living organisms, may be composed of proteins, carbs, nucleic acids, or combinations

ways drugs can be classified

pharmacological effect, chemical structure, target system, site/mechanism of action

orgo view of functional groups

specific grouping of atoms within molecules that have their own characteristic properties (reactivity), regardless of other atoms present in a molecule

pharmaceutical chemistry view of functional groups

functional groups provide specific properties and behaviors that allow drug molecules to exert their desired pharmacodynamic and pharmacokinetic effects

pharmacodynamics

what a drug does to our body, drug target, intracellular signaling pathway, chemical interaction

pharmacokinetics

what our body does to the drug, movement of drug into, through, and out of the body, the time course of absorption, distribution, metabolism, excretion (ADME)

bioavailability

ADME

acidic functional groups

polar, water soluble

acidic functional groups examples

beta-dicarbonyl groups, sulfonamides, sulfonylureas, tetrazoles, phenols, thiols, sulfates, phosphates, phosphonates

basic functional groups

polar, water soluble

basic functional gorups examples

amines, anilines, imines, hydrazine, amidines, guanidine