Drug Design and Development Strategies
Drug Design and Development
Penicillin Synthesis
In the design and development of new drugs, strategies based on what exists in nature are often applied. For example, in the design of new penicillins, three hypotheses are considered: biological synthesis, chemical synthesis, and a mixed approach. Biological synthesis, using fermentation culture mediums, yields limited side chains. Chemical synthesis, while producing a wider range of side chains, is difficult and has low yields. Therefore, a mixed approach is often preferred. This involves purifying an intermediate from fermentation, such as 6-APA, and then adding a side chain (RC(=O)-Cl) through radical addition to obtain different penicillins. Penicillin G can also be fermented, and then treated with penicillin acylase to obtain 6-APA, to which another side chain can be added.
Improving Existing Drugs
Drug design aims to increase activity, enhance interactions with the target, and improve selectivity. Strategies include group variations, structure extensions or contractions, chain extensions or contractions, ring expansions or contractions, ring variations, ring mergers, isosteric replacements, structure simplification, and rigidification.
Antibiotic Resistance Mechanisms
One resistance mechanism involves the deactivation of penicillin by β-lactamase, which breaks the β-lactam ring. Introducing a bulky acylated side chain can counteract this. Another issue is the limited spectrum of penicillin-G due to outer membrane and glycolysis. Introducing a hydrophilic group in the lateral chain increases activity against Gram-negative bacteria without affecting activity against Gram-positive bacteria. The effect of the hydrophilic group is greater when it’s connected to the α-carbon.
Valinomycin’s Selectivity for K+ over Na+
Valinomycin is a cyclic peptide ionophore that selectively binds K+ and transports it across cell membranes, disrupting normal ion flow. It neutralizes K+’s positive charge, allowing the complex to pass through the lipid bilayer. Other ionophores like nigericin (H+/K+ exchanger) and monensin (H+/Na+ exchanger) use carboxyl groups to form complexes with monovalent cations. Gramicidin A, a hydrophobic peptide, forms a channel selective for monovalent cations in the order Cs+ > Rb+ > K+ > Na+ > Li+. This channel repels anions (Cl-) due to dipoles associated with carbonyl groups.
K+ Channel Specificity
K+ channels are essential for restoring resting membrane potential after depolarization. K+ selectivity is linked to the channel’s size, which requires K+ ions to shed their hydration sphere. Water molecules are replaced by interactions with carbonyl groups in the channel. Na+ is too small and remains hydrated, preventing it from fitting in the channel.
Oxamniquine and Pharmacokinetics
Introducing nitrogen at positions A and B in oxamniquine created a pharmacokinetic problem. The nitrogen picked up H+, becoming ionized and hindering absorption. Adding an NO2 group improved absorption by capturing electrons and reducing the NH group’s ability to pick up H+, favoring the nonpolar (weak base) form for better absorption.
Penicillin and Cephalosporin Mechanism of Action
Both penicillins and cephalosporins inhibit transpeptidase, an enzyme crucial for peptidoglycan synthesis. Transpeptidase breaks the β-lactam ring in both antibiotics, leading to its inhibition and preventing peptidoglycan cross-linking.
Agonist and Antagonist: Allosteric Theory
The allosteric theory describes how receptors exist in relaxed (R) and tense (T) forms. Ligands control receptor conformation and activity. The MWC model suggests that conformational states are independent of ligand binding, while the KNF model proposes that ligand binding induces conformational changes. Both models explain how ligands act as agonists, partial agonists, or antagonists based on their affinity for R and T forms.
Neurotransmitter (NT) Strategies
Neurotransmitters are deactivated by enzymes or reuptake. Therapies can amplify NT effects using agonists, inhibiting inactivation or reuptake, or administering analogs resistant to inactivation. Inhibition can be achieved with antagonists or by inhibiting NT synthesis.
Drug Absorption: Tioconazole vs. Fluconazole
Fluconazole, derived from tioconazole, has increased polarity and solubility due to added polar groups. This change allows for systemic administration (fluconazole) compared to the oral administration of tioconazole.
Trypsin Inhibition by Benzamidine
Benzamidine is a reversible competitive inhibitor of trypsin. Its positive charge allows it to fit into the enzyme’s pocket and stabilize through electrostatic forces. Higher inhibitor affinity requires more substrate to reverse the inhibition.
L-Dopa and Carbidopa in Parkinson’s Disease
Parkinson’s disease is associated with low dopamine activity in the brain. L-Dopa is a dopamine precursor that can cross the blood-brain barrier. Carbidopa inhibits DOPA decarboxylase, allowing more L-Dopa to reach the brain and be converted to dopamine.
Penicillin Sensitivity to Acid
The β-lactam ring is unstable due to angular tension and weak electronic delocalization. Acidic environments catalyze ring opening. Adding an electron-withdrawing group to the acyl side chain can reduce the carbonyl’s electron density, making it less susceptible to nucleophilic attack and increasing acid stability.
Alkylating Agents
Alkylating agents interfere with DNA replication and transcription by covalently binding to DNA. Compounds with two alkylating groups can cross-link DNA. Nitrogen mustard and cisplatin are examples. Alkylating agents can also react with other nucleophiles, causing side reactions. An aromatic ring linked to nitrogen reduces nucleophilicity and decreases side reactions. Attaching these agents to DNA building blocks can increase their specificity for dividing cells.