The electron density changes from reactants towards the transition state of a chemical reaction is expressed as a linear combination of the state-specific dual descriptors (SSDD) of the corresponding reactant complexes. Consequently, the SSDD can be expected to bear important resemblance to the so-called natural orbitals for chemical valence (NOCV), introduced as the orbitals that diagonalize the deformation density matrix of interacting molecules. This agreement is shown for three case studies: the complexation of a Lewis acid with a Lewis base, a SN2 nucleophilic substitution reaction and a Diels-Alder cycloaddition reaction. As such, the SSDD computed for reactant complexes are shown to provide important information about charge transfer interactions during a chemical reaction.
The heparin family, which includes unfractionated heparin, low-molecular heparin and fondaparinux, is a class of drugs clinically used as intravenous blood thinner. To date, issues related to both to the reversal of anticoagulation and the blood level determination of the anticoagulant at the point-of-care remain: while the only U.S. Food and Drug Administration (FDA) approved antidote for heparin displays serious efficacy and safety drawbacks, the current assays for heparin monitoring are indirect measurements subject to their own limitations and variations. Herein, we provide an update on the numerous recent chemical approaches to tackle these issues, from which it is clear that some new antidotes and sensors for heparin certainly have the potential to exceed current clinical standards. This review aims to review a field that requires close collaborations between physicians, biologists and chemists in order to foster advances toward clinical translation. Context and challengesHeparin, which belongs to the family of glycosaminoglycans (GAGs), is a linear sulfated polysaccharide and consists of repeating disaccharide subunits of α-1,4 linked uronic acid and D-glucosamine (Figure 1). As a consequence, heparin displays the highest density of negative charges among biomacromolecules. This polyanion is widely used as an intravenous anticoagulant due to its ability to accelerate the rate at which antithrombin (AT) inhibits serine proteases within the blood coagulation cascade, most notably factor Xa and thrombin. [1][2][3][4] Polymers of various lengths such as unfractionated heparin (UFH, Mw ~ 15 kDa), low-molecular-weight heparins (LMWHs, Mw = 3.6-6.5 kDa), and the synthetic pentasaccharide fondaparinux (Mw = 1.7 kDa) are routinely delivered to patients. While UFH is used during acute thrombotic events or to maintain blood fluidity during procedures requiring extracorporeal circulation (i.e., cardio-pulmonary bypass or hemodialysis), 5,6 LMWHs and fondaparinux are prescribed to treat and/or prevent deep vein thrombosis and pulmonary embolism. 7,8 With an estimated one billion doses of heparin produced every year, heparin's market is rapidly growing, driven by the ageing of populations and the increasing incidence of cardiovascular diseases. 9 KeywordsAnticoagulants: commonly known as blood thinners, they are chemical substances that retard or inhibit the coagulation of the blood.
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