What is a Blood Clot? 9/18/2018 MEDC 604 Anti-coagulants

A) Physical Process B) Chemical Process The Clotting Process A) Physical Process B) Chemical Process Wound antithrombins factor Xa thrombin prothrombin fibrinogen fibrin (monomers) (polymer) vitamin K-dependent g-carboxylation of Glu residues coumarins platelet activation release thrombin release of of ADP generation thromboxane A2 Further activation of platelets Platelet aggregation aspirin ADP receptor antagonists GP IIb-IIIa CLOT Taken from Desai UR (2004) Med. Res. Rev. 24, 151-181. 9/18/2018 MEDC 604 Anti-coagulants

Physical Process of Clotting 9/18/2018 MEDC 604 Anti-coagulants

The Coagulation Cascade XII XIIa XI XIa IX IXa X Xa II IIa VII VIIa V Va VIII VIIIa F Fm CLOT XIII HMWK TF XIIIa PL/Ca2+ 9/18/2018 MEDC 604 Anti-coagulants

Interesting Features of the Coagulation Cascade Catalysis and Specificity of Reactions Involved in the Cascade 9/18/2018 MEDC 604 Anti-coagulants

Interesting Features of the Coagulation Cascade Polymerization 9/18/2018 MEDC 604 Anti-coagulants

Interesting Features of the Coagulation Cascade Amplification A E2 E1 C E3 D E4 F G A B X Y E2 9/18/2018 MEDC 604 Anti-coagulants

Regulation of Coagulation XII XIIa XI XIa IX IXa X Xa II IIa VII VIIa V Va VIII VIIIa F Fm CLOT XIII HMWK TF XIIIa PL/Ca2+ AT Protein C APC TM:IIa TFPI Why Regulate Clotting? 9/18/2018 MEDC 604 Anti-coagulants

Inhibitors of Clotting (Anticoagulants) Natural Anticoagulants Antithrombin, Tissue Factor Pathway Inhibitor, Protein C Natural Product-derived Anticoagulant Drugs Heparin-based anticoagulants, e.g., heparin, low molecular weight heparin, fondaparinux, idraparinux Coumarin-based anticoagulants, e.g., warfarin, acenocoumarin Hirudin (derived from leeches), lepirudin, desirudin, bivalirudin Tick anticoagulant peptide Other Anticoagulants Argatroban, melagatran, ximelagatran 9/18/2018 MEDC 604 Anti-coagulants

Inhibitors of Coagulation Structure and sequence 9/18/2018 MEDC 604 Anti-coagulants

Pentasaccharide 9/18/2018 MEDC 604 Anti-coagulants

Clinically useful coumarins and 1,3-indanediones 9/18/2018 MEDC 604 Anti-coagulants

Direct Thrombin Inhibitors HIRUDIN – Isolated from leech, hirudino medicinalis. A polypeptide consisting of 65 amino acid residues that binds thrombin in the active site as well as another site called exosite I 9/18/2018 MEDC 604 Anti-coagulants

All Anticoagulants have Significant Problems!! Our Work …. designing molecules that are radically different from all known anticoagulants using a multidisciplinary approach involving computational chemistry, organic synthesis, enzyme assays, mechanistic biochemistry, and plasma, blood and animal studies … www.people.vcu.edu/~urdesai 9/18/2018 MEDC 604 Anti-coagulants