Development of Urease Inhibitors by Fragment‐Based Dynamic Combinatorial Chemistry

Abstract

In this study, fragment-based dynamic combinatorial chemistry (DCC) was explored for the development of novel urease inhibitors. Based on a rationally designed fragment, two iteratively evolved dynamic combinatorial libraries (DCLs) were generated and screened in the presence of urease template.The best ligand identified revealed not only strong urease inhibition but also low cytotoxicity. Additionally, a possible inhibitory mechanism was elucidated in the binding kinetics study and docking simulation.

Fragment-Based Dynamic Combinatorial Chemistry for Identification of Selective α-Glucosidase Inhibitors

“…Over the past two decades, dynamic combinatorial chemistry (DCC) has been established as a powerful tool to discover biologically active lead compounds in medicinal chemistry. , Based on covalent or noncovalent reversible reactions between building blocks with complementary functional groups, spontaneous generation of dynamic combinatorial library (DCL) can be accomplished under thermodynamic control. − Due to the adaptive nature of DCL, its equilibrium can be altered by the addition of external stimuli, thereby changing the composition of the dynamic system (Figure a). − Enzyme protein is most commonly used in the screening of active components as external template . DCL driven by this type of stimulus achieves amplification of constituent(s) with higher binding affinity at the expense of other less favored combinations, resulting in a thermodynamically controlled evolutive process on molecular level. , …”

“…11 DCL driven by this type of stimulus achieves amplification of constituent(s) with higher binding affinity at the expense of other less favored combinations, resulting in a thermodynamically controlled evolutive process on molecular level. 12,13 Fragment-based drug design (FBDD) has gained wide application in the field of drug discovery in recent years due to its success in obtaining bioactive substances, and a variety of clinical drugs have been developed using this strategy. 14 FBDD starts from low-affinity binding fragments, which eventually grows into highly active compounds through fragment modification.…”

“…This inherent disadvantage of FBDD can be effectively overcome by combining with DCC to yield a one-pot substance generation and affinity screening protocol, significantly accelerating the drug R&D process. 12 Diabetes mellitus (DM) is a metabolic disease featured by elevated level of glucose in the blood due to insufficient insulin production, and it usually leads to severe complications in the liver, heart, brain, and kidneys. 18 α-Amylase (EC 3.2.1.1), which is secreted primarily by the human pancreas, is the primary enzyme responsible for converting polysaccharides to oligosaccharides.…”

“…Compared with traditional high-throughput screening (HTS), FBDD has the advantages of target specificity and cost efficiency. , Nevertheless, it still involves tedious synthesis and biological verification, same as the other conventional methods. This inherent disadvantage of FBDD can be effectively overcome by combining with DCC to yield a one-pot substance generation and affinity screening protocol, significantly accelerating the drug R&D process …”

Synthesis and Characterization of Linear Polyglycidol Derivatives: Surface Activity and Potential for Advanced Doxorubicin Delivery Application

“…The samples were diluted to appropriate concentrations with phosphate buffer saline (PBS, pH = 7.4) in the presence of various contents of GSH (0, 10.00 μM, 1.00 mM, and 10.00 mM) and measured at 25 °C. For the stability tests, DOX@ LPGE-SS-2 micelles were incubated in PBS (pH 7.4) containing 10% FBS and aqueous medium at 37 °C for different times and the particle size was measured using the same instrument. − …”