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Development of 2-(2-(3-(4-([18F]Fluoromethoxy-d2)phenyl)-7-methyl- 4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyi...

Published in Journal of medicinal chemistry

Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central nervous system disorders. 2-(2-(3-(4-([18F]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659, [18F]5) is a useful positron emission tomography (PET) ligand for imaging of PDE10A in the human brain. However, ...

The journey of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) from lab to clinic.

Published in Journal of medicinal chemistry

Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique an...

Functional Characterization of a Novel Lipopolysaccharide-Binding Antimicrobial and Anti-Inflammatory Peptide in Vitro a...

Published in Journal of medicinal chemistry

Antimicrobial peptides (AMPs) are key components of host immune defense of vertebrates against microbial invasions. Here, we report a new AMP (esculentin-1GN) characterized from the skin of the frog Hylarana guentheri. Esculentin-1GN (GLFSKKGGKGGKSWIKGVFKGIKGIGKEVGGDVIRTGIEIAACKIKGEC) with high amphipathic α-helical structure in membrane-mimetic en...

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Signi...

Published in Journal of medicinal chemistry

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases ...

Structural Basis for ( S)-3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu8 Recep...

Published in Journal of medicinal chemistry

( S)-3,4-Dicarboxyphenylglycine (DCPG) was first reported in 2001 as a potent orthosteric agonist with high subtype selectivity for the mGlu8 receptor, but the structural basis for its high selectivity is not well understood. We have solved a cocrystal structure of recombinant human mGlu8 amino terminal domain (ATD) protein bound to ( S)-DCPG, whic...

Understanding Molecular Drivers of Melanin Binding To Support Rational Design of Small Molecule Ophthalmic Drugs.

Published in Journal of medicinal chemistry

Binding of drugs to ocular melanin is a prominent biological phenomenon that affects the local pharmacokinetics and pharmacodynamics in the eye. In this work, we report on the development of in vitro and in silico tools for an early assessment and prediction of melanin binding properties of small molecules. A robust high-throughput assay has been e...

Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therap...

Published in Journal of medicinal chemistry

G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with sup...

Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction.

Published in Journal of medicinal chemistry

Fibrosis is an inadequate response to tissue stress with very few therapeutic options to prevent its progression to organ dysfunction. There is an urgent need to identify drugs with a therapeutic potential for fibrosis, either by designing and developing new compounds or by repurposing drugs already in clinical use which were developed for other in...

Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.

Published in Journal of medicinal chemistry

Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer p...

Receptor–Ligand Interaction Measured by Inductively Coupled Plasma Mass Spectrometry and Selenium Labeling

In the search for an alternative strategy to the radioactivity measurement conventionally performed to probe receptor–ligand interactions in pharmacological assays, we demonstrated that selenium labeling of the studied ligand combined with elemental mass spectrometry was as efficient and robust as the reference method but devoid of its environmenta...