Medicinal Chemistry Exam 2

Understanding drug classes by their chemical structure helps predict how they interact with biological targets. Key structural motifs correspond to specific drug actions. For example, flat planar fused aromatic rings indicate DNA intercalators, which insert between DNA base pairs disrupting function. When a planar aromatic core is combined with a positive amino group, it suggests an intercalator that also anchors to the negatively charged DNA phosphate backbone, enhancing binding. Fluoroquinolones have a scaffold containing carbonyl and carboxylate groups, acting as bacterial topoisomerase poisons that interfere with DNA replication. Molecules with two reactive electrophilic ends can form covalent bonds with DNA, acting as alkylating or cross-linking agents. Cisplatin features a platinum atom coordinated with two chloride and two ammonia ligands, functioning as a metallating agent that cross-links DNA. Enediyne systems generate radicals that cut DNA chains. Nucleoside analogues lacking a usable 3'-OH group act as chain terminators in DNA synthesis. Suicide substrates are substrate-like compounds activated by their enzyme to form irreversible inhibitors. Transition-state inhibitors mimic the high-energy tetrahedral state of enzyme reactions, binding tightly and reversibly. A messenger-like receptor ligand with an added bulky group can act as an antagonist by blocking receptor activation. Taxanes have a taxane/baccatin core with an oxetane ring and side chain, targeting tubulin. Large amphipathic macrocycles with polyene faces resemble amphotericin, forming pores in membranes.

Nucleic acids store and transmit genetic information. Purines (adenine and guanine) have fused six- and five-membered rings, while pyrimidines (cytosine and thymine) have a single six-membered ring. A nucleoside consists of a nitrogenous base plus a sugar; adding phosphate groups forms a nucleotide. Base pairing occurs between adenine-thymine (A-T) and guanine-cytosine (G-C). DNA replication copies DNA to DNA, transcription converts DNA to mRNA, and translation reads mRNA to produce proteins. Different RNAs have roles: mRNA carries codons as a blueprint; tRNA has anticodons and carries amino acids; rRNA forms ribosomes; snRNA participates in RNA processing. Restriction enzymes cut DNA at specific sequences, while ligases join DNA fragments. The wobble rule states mutations at the third codon position often do not change the amino acid. Silent mutations (e.g., UAU to UAC) do not alter amino acids; missense mutations (e.g., UAU to UUU) change the amino acid; nonsense mutations (e.g., UAU to UAA) introduce stop codons and are usually most disruptive.

Enzyme inhibitors reduce enzyme activity by different mechanisms. Competitive inhibitors bind the active site; increasing substrate concentration can overcome inhibition, so Vmax remains the same but apparent Km increases. Pure noncompetitive inhibitors bind allosterically (at a different site), decreasing Vmax without changing Km. Uncompetitive inhibitors bind only the enzyme-substrate complex allosterically, decreasing both Vmax and Km; their Lineweaver-Burk plots show parallel lines. Irreversible inhibitors form covalent bonds with nucleophilic residues in the enzyme, permanently inactivating it. Transition-state inhibitors mimic the high-energy tetrahedral state of enzyme-substrate complexes, binding tightly and reversibly. Suicide substrates are activated by the enzyme to form reactive species that irreversibly inhibit the enzyme. For example, penicillins act as irreversible inhibitors, clavulanic acid is a suicide substrate, and serine residues are common reactive sites. Lineweaver-Burk plots help distinguish inhibition types. The suicide-substrate mechanism of trifluoroalanine with alanine-transaminase involves enzyme-catalyzed formation of a reactive intermediate that covalently modifies the enzyme.

Agonists bind receptors and activate them, producing a biological effect. Partial agonists activate receptors but produce a lower maximal effect than full agonists. Antagonists bind receptors without activating them and block agonist binding. Inverse agonists reduce constitutive (basal) receptor activity below normal levels. Designing agonists involves matching binding groups, positions, and molecular size/shape to induce the correct receptor conformation (induced fit). Antagonists retain affinity but alter interactions to prevent activation. An extra aromatic ring can increase binding interactions and promote antagonist behavior. Affinity refers to the strength of binding; efficacy is the ability to produce an effect; potency is the amount of drug needed for effect. Lower EC50 values indicate greater potency and left-shifted dose-response curves. Prolonged agonist exposure causes receptor phosphorylation and rapid desensitization. Long-term antagonist exposure can cause receptor up-regulation and sensitization. Tolerance means needing more drug for the same effect; dependence leads to withdrawal symptoms if the drug is stopped. Tamoxifen and raloxifene have bulky side chains that prevent the estrogen receptor from adopting its active conformation. A tamoxifen metabolite lacking this bulky side chain mimics estrogen binding with two phenolic OH groups.

Drugs can target nucleic acids by intercalation, alkylation, chain termination, or enzyme poisoning. Intercalators slide between DNA base pairs, stabilized by pi and van der Waals interactions. Positive amino groups can bind the negatively charged DNA phosphate backbone. Dactinomycin binds the minor groove, blocking DNA unwinding and transcription. Doxorubicin and anthracyclines intercalate in the major groove and poison topoisomerase II (Topo II). Proflavine is a planar tricyclic aminoacridine intercalator. Bleomycin intercalates, binds Fe2+, and generates reactive oxygen species causing DNA breaks. Etoposide and teniposide poison Topo II without intercalation. Camptothecin poisons Topo I. Fluoroquinolones like ciprofloxacin poison bacterial topoisomerases. Alkylating agents are electrophiles that covalently bond nucleophilic DNA sites, especially guanine. Agents with two reactive groups can cross-link DNA strands. Busulfan forms interstrand guanine links. Nitrosoureas alkylate DNA and carbamoylate proteins. Cisplatin aquates in low-chloride environments to form reactive platinum species that cross-link adjacent guanines, mainly intrastrand. Mitomycin C is activated by reduction to alkylate and cross-link guanine bases. Calicheamicin forms diradicals that cut DNA chains. Nucleoside analogues like AZT and aciclovir lack a 3'-OH, causing chain termination after incorporation. Hairpin polyamides bind the minor groove. Antisense oligonucleotides pair with mRNA to block translation. miRNA/siRNA guide RISC to complementary mRNA for cleavage. Temozolomide converts to MTIC, then to a methyldiazonium ion that methylates DNA, especially O6 guanine. Review cisplatin and mitomycin activation and calicheamicin radical formation for understanding mechanisms.

Several drug classes target diverse biological molecules. SSRIs block serotonin reuptake transporters, mainly used as antidepressants. Tricyclic antidepressants can block noradrenaline reuptake. Cocaine blocks neurotransmitter reuptake but is not transported into cells by these transporters. Vinca alkaloids target tubulin and inhibit microtubule formation, disrupting cell division. Paclitaxel and taxoids also target tubulin but stabilize microtubules, preventing depolymerization. Paclitaxel features a complex baccatin III/taxane core, an oxetane ring, and a characteristic side chain. Taxoid analogues tolerate bulky 3' amide substituents, indicating a large hydrophobic binding pocket. Puromycin mimics aminoacyl-tRNA, accepting the peptide chain but terminating protein synthesis prematurely. Nutlins are small molecules that mimic amino acid contacts in protein-protein interactions. Amphotericin is amphipathic and self-assembles in fungal membranes to form pores that disrupt ion and water balance. Glycosphingolipids consist of carbohydrate, fatty acid, and sphingosine; their hydrophilic carbohydrate heads can act as antigens, such as ABO blood group labels. Sugammadex has a hydrophobic cavity that forms van der Waals contacts with rocuronium and negatively charged carboxylates that attract and anchor its positive groups. The four-atom linker in sugammadex positions carboxylates optimally; shorter linkers cannot reach, and longer ones are too flexible.

Binding affinity does not guarantee receptor activation; antagonists can bind strongly but have no activating efficacy. Potency (amount needed) is not the same as efficacy (maximum effect); a highly potent partial agonist may have lower maximal effect. Transition-state inhibitors are not necessarily irreversible; they often bind tightly but reversibly. 'Allosteric' refers to binding location, while 'noncompetitive' and 'uncompetitive' describe kinetic inhibition patterns; many noncompetitive and uncompetitive inhibitors bind allosterically. Topoisomerase II normally cuts both strands of a DNA segment, passes another duplex through, and reseals, relieving topological tension without breaking DNA continuity. Doxorubicin intercalates and poisons Topo II; etoposide poisons Topo II without intercalation. Intercalation means inserting a flat aromatic portion between base pairs; major or minor groove describes the approach and additional interactions. Cisplatin disrupts guanine-rich DNA interactions, not adenine-thymine pairs. Van der Waals and hydrophobic contacts are major contributors to rocuronium encapsulation by sugammadex; carboxylates provide electrostatic anchoring.