5.4 AI review- MedChem

A thrombus (blood clot) is composed of aggregated ____ and red blood cells within a mesh of cross‑linked fibrin.

platelets

Two coagulation pathways converge on thrombin generation: the Contact activation ( ____) pathway and the tissue factor (__________) pathway.

intrinsic; extrinsic

The tissue factor pathway is typically initiated by ____ and is a major driver of arterial thrombogenesis.

trauma

γ‑Glutamyl carboxylase converts _____ residues on Factors II, VII, IX, and X to ____ to enable Ca2+‑dependent activation.

Glu; Gla

Vitamin K hydroquinone (KH2) is oxidized to vitamin K epoxide during carboxylation and then recycled by the enzyme ____.

vitamin K epoxide reductase (VKOR)

Coumarin derivatives act as vitamin K antagonists by inhibiting ____, interrupting the vitamin K cycle.

VKOR

Clinically used warfarin is a racemic mixture in which the ____ enantiomer is >4‑fold more potent than the other.

S‑

Installing a ____ substituent at C‑4 of the coumarin ring permits sodium salt formation and improves aqueous solubility.

4‑OH (phenolic)

Dicoumarol was the first orally active anticoagulant in humans and is a natural product derived from ____ sources.

fungal

Thrombin is a serine protease that converts soluble fibrinogen into insoluble strands of ____.

fibrin

________ is a heterogeneous, highly sulfated polysaccharide mixture with mean molecular weight ≈ 15 kDa.

Unfractionated heparin (UFH)

______ typically range 4-6 kDa and show more selective anti‑Xa activity.

Low‑molecular‑weight heparins (LMWH)

_______ is a synthetic, highly sulfated pentasaccharide with improved pharmacokinetics and selective anti‑Xa action.

Fondaparinux

Heparin binding induces a ________ in antithrombin that enhances its protease inhibition

conformational change

LMWHs predominantly inhibit clotting factor ____ via antithrombin.

Xa

UFH can bridge antithrombin to both ______ and ____, whereas LMWH cannot efficiently bridge ____

- thrombin (IIa) and Xa

- IIa

Thrombin contains ________ for fibrin binding,_______ for heparin binding, and a catalytic ______

- exosite I (E1)

- exosite II (E2)

- active site

Univalent DTIs occupy the ______, while bivalent DTIs bind the _________

- thrombin active site only

- active site plus exosite I (E1)

Hirudin is a 65‑amino‑acid protein that forms a tight 1:1 complex with thrombin and inhibits both __________

free and ‑bound fibrin

Lepirudin and desirudin are recombinant hirudin derivatives that act as ____ DTIs with nearly irreversible functional inhibition.

bivalent

Argatroban is a peptidomimetic, competitive, ____ DTI that selectively targets the catalytic site.

univalent

The marketed argatroban contains 21‑(R) and 21‑(S) diastereomers, with the ____ isomer approximately twice as potent.

S‑

Dabigatran etexilate is an orally active prodrug; the active dabigatran features a ____ headgroup that binds _________

- benzamidine (basic)

- thrombin S1.

Dabigatran engages thrombin subsites ____ and partially S4.

S1 and S2

Thromboxane A2 (TXA2) is a labile mediator that induces platelet aggregation; its synthesis is blocked by inhibiting ____.

COX‑1

Aspirin irreversibly acetylates a catalytic ______ in platelet COX‑1, suppressing TXA2 formation for the platelet lifespan.

serine residue (Ser529)

________ shares aspirin's COX‑1 acetylation mechanism but exhibits distinct PK/PD properties.

Triflusal

PDE3 degrades ______ to _____; selective PDE3 inhibition elevates intracellular ____ and inhibits platelet aggregation.

- cAMP to AMP

- cAMP

Cilostazol is a selective quinolinone derivative that inhibits ____ without significant activity on ____

- PDE3A

- PDE1/2/4

Ticlopidine, clopidogrel, and prasugrel are ____ that require _________

- thienopyridine prodrugs

- bioactivation to thiol metabolites

Clopidogrel and ticlopidine require CYP‑mediated oxidation to a 2‑oxo intermediate, then hydrolysis to a ____ that reacts with P2Y12.

thiol

Prasugrel activation involves ____ followed by further metabolic steps to yield the active thiol.

esterases

Active thienopyridine metabolites form a _______ with a cysteine on P2Y12, producing ____ inhibition.

- disulfide bond

- irreversible

Ticagrelor and cangrelor bind P2Y12 ____ and are reversible inhibitors.

allosterically (non‑ADP site)

Ticagrelor can allow ADP binding yet locks the receptor in an inactive conformation that prevents ____ coupling.

G‑protein

Fibrinogen bridges adjacent platelets via _________; antagonism prevents ________

- GPIIb/IIIa

- cross‑linking and platelet aggregation

Abciximab is a chimeric human-mouse 7E3 Fab fragment directed against ______

GPIIb/IIIa

Eptifibatide is a cyclic heptapeptide whose ____ motif confers high specificity for GPIIb/IIIa.

KGD (Lys‑Gly‑Asp)

Tirofiban is a nonpeptide, ____ that mimics the________ to reversibly block GPIIb/IIIa.

- peptidomimetic ('fiban')

- RGD motif

Plasminogen is converted to plasmin by ____ to dissolve fibrin in newly formed clots.

tissue‑type plasminogen activator (t‑PA)

Alteplase is unmodified ______ produced by recombinant DNA technology.

human t‑PA

Reteplase is a recombinant ________ lacking the first 172 amino acids, yielding a longer half‑life but reduced fibrin selectivity.

deletion mutant of t‑PA

Tenecteplase contains three substitutions (T103N, N117Q, KHRR296‑299→AAAA) that ________ and _______

prolong half‑life and increase fibrin specificity

PAI‑1 inhibits t‑PA; tenecteplase shows ____ PAI‑1 binding versus alteplase, enhancing activity.

reduced

Compared with alteplase, tenecteplase exhibits __________

higher fibrin specificity.

Which best explains why a 4‑OH substituent is privileged in warfarin SAR?

A. Enhances VKOR binding via H‑bonding only

B. Increases acidity enabling water‑soluble salt formation

C. Prevents first‑pass metabolism entirely

D. Selectively targets factor Xa

B. Increases acidity enabling water‑soluble salt formation

Relative to LMWH, UFH more effectively inhibits thrombin (IIa) because UFH:

A. Is less sulfated and diffuses into platelets

B. Bridges antithrombin and IIa due to sufficient chain length

C. Directly acetylates thrombin Ser195

D. Acts as a bivalent DTI

B. Bridges antithrombin and IIa due to sufficient chain length

Which pairing is MOST accurate regarding thrombin binding modes?

A. Dabigatran—bivalent (E1 + active site)

B. Argatroban—univalent active‑site inhibitor

C. Lepirudin—univalent competitive inhibitor

D. Hirudin—E2 allosteric modulator

B. Argatroban—univalent active‑site inhibitor

Which mechanistic statement about thienopyridines is CORRECT?

A. They are active drugs that reversibly block ADP at P2Y12

B. Their thiol metabolites form a disulfide with P2Y12 to irreversibly inhibit signaling

C. They all require CYP2C19 exclusively for activation

D. They competitively displace fibrinogen from GPIIb/IIIa

B. Their thiol metabolites form a disulfide with P2Y12 to irreversibly inhibit signaling

Ticagrelor reduces ADP signaling primarily by:

A. Covalently modifying the ADP site

B. Allosterically locking P2Y12 in an inactive conformation

C. Depleting ADP via ectonucleotidase activation

D. Inhibiting PLCβ downstream of Gi

B. Allosterically locking P2Y12 in an inactive conformation

The 2,000‑fold acceleration of antithrombin's protease inhibition upon heparin binding is BEST attributed to:

A. Formation of a covalent AT‑protease adduct

B. A conformational change that increases protease affinity

C. Heparin acting as a catalytic nucleophile

D. Direct blockade of the protease active site by heparin

B. A conformational change that increases protease affinity

Which property distinguishes reteplase from alteplase?

A. Greater fibrin specificity

B. Shorter half‑life

C. Deletion of the N‑terminal 172 amino acids

D. Covalent inhibition of plasminogen

C. Deletion of the N‑terminal 172 amino acids

Eptifibatide's selectivity for GPIIb/IIIa is primarily driven by which embedded motif?

A. RGD

B. KGD

C. KGE

D. RGE

B. KGD

Which change MOST directly explains tenecteplase's increased activity compared with alteplase?

A. Enhanced binding to PAI‑1

B. Reduced binding to PAI‑1 and prolonged half‑life via three mutations

C. Loss of fibrin specificity via catalytic site alteration

D. Ability to activate prothrombin

B. Reduced binding to PAI‑1 and prolonged half‑life via three mutations

Which statement correctly contrasts UFH and LMWH pharmacology?

A. LMWH predominantly inhibits IIa, UFH predominantly inhibits Xa

B. Both require antithrombin but LMWH shows preferential anti‑Xa activity

C. UFH is a direct thrombin inhibitor, LMWH is indirect

D. LMWH binds E1 on thrombin to cause irreversible inhibition

B. Both require antithrombin but LMWH shows preferential anti‑Xa activity