| Type | Description | Example | Site | Active site shape similar? | ↑ substrate concentration | ↑ inhibitor concentration | Behavior with substrate | Resistance / notes |
|---|---|---|---|---|---|---|---|---|
| Competitive (continued from previous page) | … hydrophobic interactions and ionic bonds. | the enzyme at the same time | real substrate | substrate (substrate 가 낮으면 ie inhibition 술 석성), 따라서 IC50 이 Ki 보다 매우 커야 안심. than in allosteric. Therefore, resistance to a competitive inhibitor occur a lower frequency than resistance a non-competitive inhibitor. | ||||
| Non-competitive | the inhibitor may bind to the enzyme whether or not the substrate has already been bound. | Takeda's GCS inhibitor | allosteric sites (i.e. locations other than its active site) → then, the active site 의 모양이 변해서 substrate 도 못 binding | Not similar | ↓ | No change | the extent of inhibition depends only on the concentration of the inhibitor (substrate 가 낮건 석건 inhibition 괜잖음, ie IC50 안 변함) | 이게? 이상석일 수 있겠군 |
| Uncompetitive | the inhibitor binds only to the substrate-enzyme complex | Rare: LDH by oxalate; inhibition of alkaline phosphatase by L-phenylalanine, venglustat | Not similar | ↓ | ↓ | When ↑ substrate concentration → ↑ inhibition (식관과 반대니 주의요!), might be less effective at lower levels of its subtrate (?), 그러나 substrate 가 낮은 경우 product 도 낮을 테니, 어차피 inhibitor 의 목석달성과 같으니 이건 무의미하지 않나? | 약작용이 느릴 가능성 (inhibitor can only bind enzyme when enzyme-substrate complex formed.) 그러나 생제내에서 이미 equilibrium 으로 열심히 양방향 cycle 이 돌고있겠지, Rather, the inhibitor bind the enzyme only in the presence of substrate. → implication: ↑ substrate level + ↑ binding efficiency → But, chronic administration → the substrate will accumulate, so binding efficiency be restored. The onset of Pharmacologic effect would be slow. | |
| Mixed | the inhibitor can bind to the enzyme at the same time as the enzyme's substrate. However, | Generally allosteric sites → then affects the binding of the substrate, and vice versa. | Yes | can be reduced, but not overcome by increasing concentrations of substrate. | ||||
| Irreversible | via covalent bond formation | Poison, Allopurinol – the anti-gout drug, penicillin, aspirin, 요즘은 신약 거의 없겠군 | yes | Irreversible inhibitors display time-dependent inhibition and their potency therefore cannot be characterised by an IC50 value |
maximum velocity (Vmax) of the reaction
Km : the amount of substrate needed to reach half of the Vmax
Binding Affinity
| Inhibition constant |
- also represents a dissociation constant, but more narrowly for the binding of an inhibitor to an enzyme - Ki values only accurately report a binding constant when the kinetic mechanism is correctly identified (eg competitive vs non-competitive) | ||
|---|---|---|---|
| Dissociation constant |
- a more general, all-encompassing term. - Kd' is preferred when the binding is measured more directly (e.g. by fluorescence quenching, isothermal titration calorimetry, or surface plasmon resonance). he smaller the dissociation constant, the more tightly bound the ligand is, or the higher the affinity between ligand and protein. Enzyme 과 약 과의 관계! Kd is the equilibrium binding constant. It is the concentration of unbound drug at which 50% of binding sites are occupied. | PL ⇌Kd P + L Kd = [P][L] / [PL] = k−1 / k1 | the equilibrium between the ligand-protein complex and the dissociated components. - (어떤 상황에서는) 선제 enzyme 중 실반이 drug 과 결합되어 있는 대의, free drug 의 동도 인 셈. |
| Receptor occupancy | RO(%) = Cu.b / (Kd + Cu.b) 부슨 약이던 간에, Kd value 에서 50% RO |
is not only a function of inhibitor binding affinity (Ki), but also on the relative amount of residual turnover rate of the ESI complex (k’cat). Ie enzyme 과 약과 그 ogical product (eg acetyl-tubulin, 4MUG) 들과의 종체적 관계.
PD relationship
| max |
the maximum effect (Emax) the concentration producing 50% of the maximum effect (C50). | Conc = C50 × Effect / (Emax − Effect) E = Emax × Conc / (C50 + Conc) | portion of the curve between 20 and 80% of Emax is approximately a stratight line. 16 times change in conc is needed to change the effect from 20 to 80% of Emax. |
| sigmoid Emax: for drugs with steeper curve | E = Emax × ConcHill / (C50Hill × ConcHill) | ||
| dose-time | Doubling the dose will increase the duration of effect by 1 half life (Holford 2017) | ||
| initial concentration-Effect: three scenarios (Holford 2017) | If initial concentrations being above the C50 (for most of the day), then drugs which have short half-lives can have big effects even if the dosing interval is many half-lives. Ie There is little change in effect despite big changes in concentration. Eg. After more than 5 half-lives … | ||
| time course of effects : three scenarios (Holford 2017) |
In between the C20 and C80 the time course of loss of drug effect is almost a straight line. When concentrations are very low (less than C20) the curve is almost exponential. The time course of concentration and effect are almost parallel to one another. This is the only time it makes sense to describe the effect as having a 'half-life'. 1. Drug effects are immediately related to observed drug concentration (e.g. in plasma) 2. Drug effects are delayed in relation to observed drug concentration |
|---|
Uncertain Spans
- “(substrate 가 낮으면 ie inhibition 술 석성)” — Competitive 행 마지막 셀의 한글, ‘술 석성’이 OCR 오인식이거나 잘림으로 보이며 ‘줄 적성’ / ‘울 석성’ 등 후보 모두 의미 불분명. 시각적으로 가장 가까운 형태로 전사.
- “이게? 이상석일 수 있겠군” — Non-competitive 행 마지막 셀, ‘이상적’ 또는 ‘이상석’ 사이 모호. OCR/시각 모두에서 ‘석’에 가깝게 보여 그대로 전사.
- “선제 enzyme 중 실반이 drug 과 결합되어 있는 대의, free drug 의 동도 인 셈” — 한글 OCR 오인식이 다수: ‘전체/일반/때의/농도’를 ‘선제/실반/대의/동도’로 인식. 글자 그대로 전사하고 보정하지 않음.
- 하단 ‘time course of effects: three scenarios (Holford 2017)’ 표 — 사진 잘림으로 항목 3 이후가 보이지 않으며, 항목 1·2 만 전사.