From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

Nozal, Vanesa; García‐Rubia, Alfonso; Cuevas, Eva P.; Pérez, Concepción; Tosat‐Bitrián, Carlota; Carro, Eva; Ramírez, David; Palomo, Valle; Martı́nez, Ana

doi:10.1002/anie.202106295

Cited by 12 publications

(5 citation statements)

References 40 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These two sites are . Again, these entities are made of two structural moieties, each designed to recognise a different target [14][15][16][17][18][19][20]. However, this time, the chemical link between these elements is not cleavable.…”

Section: Non-dissociable Conjugatesmentioning

confidence: 99%

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Guiselin,

Lecoutey,

Rochais

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug–drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.

show abstract

Section: Non-dissociable Conjugatesmentioning

confidence: 99%

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Guiselin,

Lecoutey,

Rochais

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Furthermore, computational studies confirmed how these compounds adequately accommodate into the long and rather narrow BACE1 catalytic site. Finally, they employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs [82].…”

Section: Computational Polypharmacology Applied To Multitarget Drug D...mentioning

confidence: 99%

New Drug Design Avenues Targeting Alzheimer’s Disease by Pharmacoinformatics-Aided Tools

et al. 2022

Self Cite

View full text Add to dashboard Cite

Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer’s disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

show abstract

“…Alzheimer’s disease (AD), the most prevalent neurodegenerative disease, is one of such multifactorial diseases that lack an effective treatment, which would greatly benefit from the development of multitarget drugs. − A key step of multitarget drug design is the selection of the targets, whose modulation should result in additive or synergistic effects, preferably on key pathogenic mechanisms …”

Section: Introductionmentioning

confidence: 99%

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

et al. 2022

View full text Add to dashboard Cite

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer’s disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)–TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration.

show abstract

From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

Cited by 12 publications

References 40 publications

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

New Drug Design Avenues Targeting Alzheimer’s Disease by Pharmacoinformatics-Aided Tools

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

Contact Info

Product

Resources

About