Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
A adenosine receptor (AAR) positive allosteric modulators (PAMs) (2,4-disubstituted-1-imidazo[4,5-]quinolin-4-amines) allosterically increase the of AAR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse AARs. The chain length, functionality, and attachment position were varied to modulate AAR PAM activity. For example, (MRS8247, -alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's and potency ([S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved AAR PAM activity through rational design based on an extrahelical, lipidic binding site.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636968 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.4c00944 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Identification of temperature-insensitive residues in regulating SARS-CoV-2 variants-human ACE2 interaction-a study of molecular dynamics simulation.
Phys Chem Chem Phys
September 2025
School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
The COVID-19 pandemic remains a global health crisis, with successive SARS-CoV-2 variants exhibiting enhanced transmissibility and immune evasion. Notably, the Omicron variant harbors extensive mutations in the spike protein's receptor-binding domain (RBD), altering viral fitness. While temperature is a critical environmental factor modulating viral stability and transmission, its molecular-level effects on variant-specific RBD-human angiotensin-converting enzyme 2 (hACE2) interactions remain underexplored.
View Article and Find Full Text PDFEffects of apigenin on the function of human α7-nicotinic acetylcholine receptors expressed in oocytes.
Nat Prod Res
March 2025
Department of Pharmacology and Therapeutics, College of Pharmacy, Kuwait University, Safat, Kuwait.
The effects of apigenin, a plant flavonoid, were investigated using the two-electrode voltage-clamp technique on the function of the cloned α7 subunit of the human nicotinic acetylcholine (α7-nACh) receptor expressed in oocytes. Currents induced by ACh (100 μM) were reversibly potentiated by apigenin with an EC value of 5.4 µM in a voltage-independent manner.
View Article and Find Full Text PDFUnravelling the novel mode of action of the spinosyn insecticides: A 25 year review.
Pestic Biochem Physiol
November 2025
Corteva Agriscience, Indianapolis, IN 46268, USA; Retired - Present address Agrilucent LLC, Morro Bay, CA 93442, USA.
Since their registration more than 25 years ago, the spinosyns have become a significant insect management tool in farmers' battles to protect crop quality and yield. Spinosad (Qalcova™ active) and spinetoram (Jemvelva™ active), the two members of the Insecticide Resistance Action Committee (IRAC) Group 5 nicotinic acetylcholine receptor (nAChR) allosteric modulators Site I, class of insecticides, have proven highly effective at controlling chewing insect pests on over 250 different crops. Their importance as an integral rotation partner in insect pest management programs has stimulated a large body of research into their mode of action (MoA) and mechanisms of resistance.
View Article and Find Full Text PDFGABA receptor availability in clinical high-risk and first-episode psychosis: a [C]Ro15-4513 positron emission tomography study.
Mol Psychiatry
September 2025
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 16 De Crespigny Park, London, SE5 8AB, UK.
Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABA receptors containing the α5 subunit (GABARα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia.
View Article and Find Full Text PDFRecent advances in computational strategies for allosteric site prediction: Machine learning, molecular dynamics, and network-based approaches.
Drug Discov Today
September 2025
Department of Pharmaceutical and Artificial-Intelligence Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Cen
The landscape of allosteric drug discovery is undergoing a transformative shift, driven by the integration of three computational approaches: machine learning (ML), molecular dynamics (MD) simulations, and network theory. ML identifies potential allosteric sites from multidimensional biological datasets; MD simulations, empowered by enhanced sampling algorithms, reveal transient conformational states; and network analyses uncover communication pathways, further aiding in site identification. Their synergy enables rational allosteric modulator design.
View Article and Find Full Text PDF