Slow-binding kinetics

In contrast to unfractionated heparin, the factor Xa inhibitor tick anticoagulant peptide (TAP) effectively inhibited coronary arterial thrombosis in a canine electrolytic injury model (57). TAP was also effective in inhibition of the procoagulant properties of whole blood clots in vitro however, it was stated that TAP might be not optimal due to its slow binding kinetics (54). Meanwhile, several low molecular weight direct factor Xa inhibitors are in clinical development (Table I), some of them specifically for the treatment and secondary prevention of ACS. DX-9065a, ZK-807834 and otamixaban have been intensively characterized in vitro and in vivo and are in clinical investigations for the treatment of acute arterial thrombosis. 

Notably, for some benzamides a time-dependent increase in affinity has been observed [34, 56, 57]. Bressi et al. proposed that disruption of an intramolecular hydrogen bond of the NH2 group to the carbonyl oxygen is required for tight binding and may cause the slow binding kinetics [34]. 

It should be said that extreme rigidity is often undesirable, because it may prevent access to the binding site and slow binding kinetics. Moreover, it may not be possible to design a completely rigid receptor with precise complementarity to the target. A limited degree of flexibility allows the receptor to settle around its substrate, and is often present in effective systems. 

Recently, a biomimetic ion imprinted technique (that is, using metal ion as template) has become a potential tool for the preparation of robust materials that have the ability to specifically bind a metal ion species with high selectivity. However, most of these traditional imprinting techniques suffer from low binding capacity, poor site accessibility, and slow binding kinetics because of most imprinted sites were embedded in high rigid polymer matrix interior. 

---