Contemporary paradigms for cholinergic ligand design guided by biological structure

Spirituality in Contemporary Paradigms: An Integrative Review

Background: As two of the most prominent cultural components, spirituality and religion give sense to our human values, conducts, and experiences. The spiritual dimension is one of the four significant aspects of holistic care. However, the diversity of views has resulted in different interpretations of the reality of spirituality and its origins and consequences. Aim: This study aimed to exami...

Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement

The DOT1L lysine methyltransferase has emerged as a validated therapeutic target in MLL-rearranged (MLLr) acute leukemias. Although S-adenosylmethionine competitive inhibitors have demonstrated pharmacological proof-of-principle in MLLr-leukemia, these compounds require further optimization to improve cellular potency and pharmacokinetic stability. Limiting DOT1L inhibitor discovery and ligand ...

The design process: properties, paradigms, and structure

In this paper, we examine the logic and methodology of engineering design from the perspective of the philosophy of science. The fundamental characteristics of design problems and design processes are discussed and analyzed. These characteristics establish the framework within which different design paradigms are examined. Following the discussions on descriptive properties of design, and the p...

The crisis of the contemporary paradigms

Rational Ligand Design for the Arylation of Hindered Primary Amines Guided by Reaction Progress Kinetic Analysis

We report the Pd-catalyzed arylation of very hindered α,α,α-trisubstituted primary amines. Kinetics-based mechanistic analysis and rational design have led to the development of two biarylphosphine ligands that allow the transformation to proceed with excellent efficiency. The process was effective in coupling a wide range of functionalized aryl and heteroaryl halides under mild conditions.