Effect of thiol compounds on human complement component C4

Abstract

Thiol compounds have been investigated as inhibitors of the covalent binding reaction of human complement protein C4 using Sepharose-C1s as a combined activating and binding surface. o- and p-substituted aminothiophenols are equally effective inhibitors, whereas the m-substituted compound is a less potent inhibitor. The anti-hypertensive drug captopril is also shown to inhibit the covalent binding reaction. A comparison of the effects of these compounds on the covalent binding reaction of isolated C4A and C4B has been made. Results suggest that a Pro-to-Leu substitution in C4B is likely to account for the differences in inhibitory potency of C4B compared with C4A observed with the aromatic inhibitors.

Investigating the Selectivity of Metalloenzyme Inhibitors

“…The use of only a few MBGs limits the chemical space being explored for the development of new therapeutics, particularly in light of the pharmacokinetic liabilities of inhibitors that contain hydroxamic acid 3, 7-10 and thiol MBGs. 11,12 …”

“…A search of the Protein Data Bank (PDB) for metalloprotein inhibitors show that the hydroxamic acid is the most common MBG, followed by carboxylic acids, thiols, and phosphonates. The use of only a few MBGs limits the chemical space being explored for the development of new therapeutics, particularly in light of the pharmacokinetic liabilities of inhibitors that contain hydroxamic acid ,− and thiol MBGs. , …”

“…The use of only a few MBGs limits the chemical space being explored for the development of new therapeutics, particularly in light of the pharmacokinetic liabilities of inhibitors that contain hydroxamic acid 3,7−10 and thiol MBGs. 11,12 There appears to be a common opinion that inhibitors containing MBGs are more promiscuous than other small molecule compounds leading to off-target effects. These effects include indiscriminate metalloenzyme inhibition or metal ion disregulation by metal ion removal from nontarget metalloproteins, thus a perception of greater risk in obtaining clinically successful therapeutics.…”

Understanding the Structure–Activity Relationship through Density Functional Theory: A Simple Method Predicts Relative Binding Free Energies of Metalloenzyme Fragment-like Inhibitors

“…In contrast, the exploration of the chemical space for MBGs has been limited, as only four classes (hydroxamic acids, thiols, carboxylic acids, and phosphonates/phosphinates) are principally used at present . This is a limiting factor to the development and the optimization of new and more potent drugs, considering the poor pharmacokinetic properties of hydroxamic acids ,− and thiols. , More recently, the use of libraries of fragment-like compounds designed to bind to metal centers in fragment-based drug discovery (FBDD) was introduced to overcome the lack of chemical diversity among MBGs and their poor optimization . The exploration of the binding site is more effective when fragments are used compared to sterically hindered large molecules, and in general this approach leads to good ligand efficiencies …”