NAD Metabolism and Related Drug Compounds

Nicotinamide adenine dinucleotide (NAD) is a long-known universal coenzyme for cellular redox reactions that takes metabolic origin from the B3 vitamin “niacin”; in recent times, it has also been found to participate as a consumed substrate in an increasingly diverse range of cellular reactions and processes, including signal transduction, DNA repair, and post-translational protein modifications. Because of that, in recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting the interactions of NAD with NAD-dependent enzymes. Further, enzymes involved in de novo biosynthesis, salvage pathways, and downstream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for discovering and developing novel treatments for medical conditions, such as cancer, neurodegeneration, aging, etc. Industrial and academic groups have produced structurally diverse molecules, which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics. Not long ago, scientists from AstraZeneca analyzed interactions of NAD-binding motifs of approximately 500 NAD-dependent human enzymes towards NAD itself or its analogues and, based on more than 2000 crystal structures, they came to the conclusion that the NAD-binding protein class is largely underrepresented in drug discovery. There are nearly 500 human protein kinases and their inhibitors, which bind at the ATP-binding domain of these enzymes and have been successfully developed and are now on the market. In contrast, only a few drugs interacting with the NAD-binding domain of NAD-dependent enzymes have been approved. On the other hand, pyridines and niacin-related compounds are also environmentally and dietarily available, often abundantly too, as a consequence of human activities or behaviors, e.g., when pesticides or food additives are used in agriculture or in the food industry. These compounds, exactly like any other pyridine-like drug, may interfere variously with endogenous NAD metabolism of cells, thus, becoming fully accessible and eventually dangerous for human health. Recent accumulating evidence suggests that such environmental toxicity is possible and likely mediated by off-targeting effects on NAD metabolism. This Special Issue will focus on NAD metabolism and the latest developments and discovery of small-molecule regulators acting within this pathway, i.e., activators or inhibitors, both naturally occurring and synthetic. One focus is on the NAD-dependent enzymes that are linked to selected disorders or diseases and on their drug targeting for therapy. Moreover, outside this, it can also be focused on the environmental pyridines still “orphan” of function or missing their targets. Original research articles, perspectives, and reviews on the discovery, mechanism of action, characterization, validation, comparative analysis, structural investigation, etc., are all welcome.