Molecular Hybridization

Zhang, Shijun; Saathoff, John M.; Li, He

doi:10.1016/b978-0-08-101011-2.00008-8

Cited by 7 publications

(4 citation statements)

References 96 publications

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“…To switch off a cholinergic signal, ACh is catabolized by the acetylcholinesterase (AChE) which hydrolyzes the ester of the neurotransmitter to acetic acid and choline. The enzyme also appears to be involved in the aggregation of Aβ by a peripheral anionic site (PAS) in addition to its classical enzymatic hydrolysis of ACh [96,97]. AChE inhibitors compensate the cholinergic tone in the synaptic transmission and thus, because of an augmenting ACh concentration, usually relieve the symptoms and can decrease the rate of cognitive decline for some months.…”

Section: Acetylcholinesterase (Ache)mentioning

confidence: 99%

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

Volpato

Holzgrabe

2018

Molecules

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The cholinergic hypothesis has been reported first being the cause of memory dysfunction in the Alzheimer’s disease. Researchers around the globe have focused their attention on understanding the mechanisms of how this complicated system contributes to processes such as learning, memory, disorientation, linguistic problems, and behavioral issues in the indicated chronic neurodegenerative disease. The present review reports recent updates in hybrid molecule design as a strategy for selectively addressing multiple target proteins involved in Alzheimer’s disease (AD) and the study of their therapeutic relevance. The rationale and the design of the bifunctional compounds will be discussed in order to understand their potential as tools to investigate the role of the cholinergic system in AD.

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Section: Acetylcholinesterase (Ache)mentioning

confidence: 99%

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

Volpato

Holzgrabe

2018

Molecules

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“…Chemical hybridization and fragment merging techniques, which generate novel small-molecule scaffolds by combining functional groups from different inhibitors and joining separately binding fragments, respectively, have yielded several novel inhibitor series with improved properties. − Using the former approach, we recently reported two series of inhibitors of P. vivax NMTs ( 12 and 30 series) with SIs reaching greater than 250 while maintaining IC 50 values less than 100 nM .…”

Section: Introductionmentioning

confidence: 99%

Exploring Subsite Selectivity within Plasmodium vivax N-Myristoyltransferase Using Pyrazole-Derived Inhibitors

Rodríguez-Hernández,

Fenwick,

Zigweid

et al. 2024

J. Med. Chem.

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N-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between Plasmodium vivax and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report PvNMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity. Various functional groups are appended to a pyrazole moiety in the inhibitor to target a pocket formed beneath the peptide binding cleft. The inhibitor core group polarity, lipophilicity, and size are also varied to probe the water structure near a channel. Selectivity index values range from 0.8 to 125.3. Cocrystal structures of two selective compounds, determined at 1.97 and 2.43 Å, show that extensions bind the targeted pocket but with different stabilities. A bulky naphthalene moiety introduced into the core binds next to instead of displacing protein-bound waters, causing a shift in the inhibitor position and expanding the binding site. Our structure−activity data provide a conceptual foundation for guiding future inhibitor optimizations.

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“…In this lieu, the hybridization of natural products' fragments with other fragments from natural or synthetic origin can afford potential bioactive compounds [18][19][20]. In principle, hybridization is a drug design strategy that extends beyond natural products and proved fruitful in achieving potential bioactive multifunctional molecules [20][21][22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Repurposing of Rosmarinic Acid-β-Amino-α-Ketoamide Hybrids as Antileishmanial Agents

Hassan,

Bayoumi,

El-Sayed

et al. 2023

Pharmaceuticals

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A series of rosmarinic acid-β-amino-α-ketoamide hybrids were synthesized and rationally repurposed towards the identification of new antileishmanial hit compounds. Two hybrids, 2g and 2h, showed promising activity (IC50 values of 9.5 and 8.8 μM against Leishmania donovani promastigotes, respectively). Their activities were comparable to erufosine. In addition, cytotoxicity evaluation employing human THP-1 cells revealed that the two hybrids 2g and 2h possess no cytotoxic effects up to 100 µM, while erufosine possessed cytotoxicity with CC50 value of 19.4 µM. In silico docking provided insights into structure–activity relationship emphasizing the importance of the aliphatic chain at the α-carbon of the cinnamoyl carbonyl group establishing favorable binding interactions with LdCALP and LARG in both hybrids 2g and 2h. In light of these findings, hybrids 2g and 2h are suggested as potential safe antileishmanial hit compounds for further development of anti-leishmanial agents.

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Molecular Hybridization

Cited by 7 publications

References 96 publications

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer’s Disease

Exploring Subsite Selectivity within Plasmodium vivax N-Myristoyltransferase Using Pyrazole-Derived Inhibitors

Design, Synthesis, and Repurposing of Rosmarinic Acid-β-Amino-α-Ketoamide Hybrids as Antileishmanial Agents

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