Many Drugs Act as Enzyme Inhibitors
The goal of pharmacology is to identify agents that can:
1. Destroy or impair the growth, invasiveness, or development of invading pathogens.
2. Stimulate endogenous defense mechanisms.
3. Halt or impede aberrant molecular processes triggered by genetic, environmental, or biologic stimuli with minimal perturbation of the host’s normal cellular functions.
By virtue of their diverse physiologic roles and high degree of substrate selectivity, enzymes constitute natural targets for the development of pharmacologic agents that are both potent and specific. Statin drugs, for example, lower cholesterol production by inhibiting the enzyme HMG-CoA reductase, while emtricitabine and tenofovir disoproxil fumarate block replication of the human immunodeficiency virus by inhibiting the viral reverse transcriptase. Pharmacologic treatment of hypertension often includes the administration of an inhibitor of angiotensin converting enzyme, thus lowering the level of angiotensin II, a vasoconstrictor.
Enzyme Kinetics Defines Appropriate Screening Conditions
Enzyme kinetics plays a crucial role in drug discovery. Knowledge of the kinetic behavior of the enzyme of interest is necessary, first and foremost, to select appropriate assay conditions for detecting the presence of an inhibitor. The concentration of substrate, for example, must be adjusted such that sufficient product is generated to permit facile detection of the enzyme’s activity without being so high that it masks the presence of an inhibitor. Second, enzyme kinetics provides the means for quantifying and comparing the potency of different inhibitors and defining their mode of action. Noncompetitive inhibitors are particularly desirable, because—by contrast to competitive inhibitors—their effects can never be completely overcome by increases in substrate concentration.
Most Drugs Are Metabolized In Vivo
Drug development often involves more than the kinetic evaluation of the interaction of inhibitors with the target enzyme. In order to minimize its effective dosage, and hence the potential for deleterious side effects, a drug needs to be resistant to degradation by enzymes present in the patient or pathogen, a process termed drug metabolism. For example, penicillin and other β-lactam antibiotics block cell wall synthesis in bacteria by irreversibly inactivating the enzyme alanyl alanine carboxypeptidase-transpeptidase. Many bacteria, however, produce β-lactamases that hydrolyze the critical β-lactam function in penicillin and related drugs. One strategy for overcoming the resulting antibiotic resistance is to simultaneously administer a β-lactamase inhibitor with a β-lactam antibiotic.
Metabolic transformation is sometimes required to convert an inactive drug precursor, or prodrug, into its biologically active form. 2′-Deoxy-5-fluorouridylic acid, a potent inhibitor of thymidylate synthase, a common target of cancer chemotherapy, is produced from 5-fluorouracil via a series of enzymatic transformations catalyzed by a phosphoribosyl transferase and the enzymes of the deoxyribonucleoside salvage pathway. The effective design and administration of prodrugs requires knowledge of the kinetics and mechanisms of the enzymes responsible for transforming them into their biologically active forms.
