Development of a Raltegravir-based Photoaffinity-Labeled Probe for Human Immunodeficiency Virus-1 Integrase Capture

Abstract

Photoaffinity labeling (PAL) is one of the upcoming and powerful tools in the field of molecular recognition. It includes the determination of dynamic parameters, such as the identification and localization of the target protein and the site of drug binding. In this study, a photoaffinity-labeled probe for full-length human immunodeficiency virus-1 integrase (HIV-1 IN) capture was designed and synthesized, following the structure of the FDA-approved drug Raltegravir. This photoprobe was found to retain the HIV IN inhibitory potential in comparison with its parent molecule and demonstrates the ability to label the HIV-1 IN protein. Putative photoprobe/inhibitor binding sites near the catalytic site were then identified after protein digestion coupled to mass and molecular modeling analyses.

Exploring RdRp–remdesivir interactions to screen RdRp inhibitors for the management of novel coronavirus 2019-nCoV

“…The temperature was fixed at 310 K using the Nose–Hoover method as the thermostat and pressure of 1 bar using Berendsen barostat. The root-mean-square-deviation (RMSD) value was calculated to determine the stability of the complex after the time period of 20 ns [ 28 ].…”

Interaction Studies between Carbonic Anhydrase and a Sulfonamide Inhibitor by Experimental and Theoretical Approaches

“…Recently, we reported the incorporation of photoreactive groups into diketoacid (DKA)-based HIV-integrase (IN) inhibitors for the identification of the DKA binding site on the IN protein . Continuing this kind of study, in this Letter, we aimed at evaluating the potential of this approach to obtain information on the molecular recognition process between human carbonic anhydrases (hCAs) and sulfonamide inhibitors.…”

“…Recently, we reported the incorporation of photoreactive groups into diketoacid the IN protein. 12 Continuing this kind of study, in this Letter, we aimed at evaluating the potential of this approach to obtain information on the molecular recognition process between human carbonic anhydrases (hCAs) and sulfonamide inhibitors. hCAs are a family of zinc enzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and proton.…”

“…Finally, photoprobe 3 was obtained in good yield by the amidation of the intermediate 7 12 and p-sulfamoylcarboxylic a c i d ( 8 ) i n t h e p r e s e n c e o f 1 -e t h y l -3 -( 3dimethylaminopropyl)carbodiimide (EDC) and N-hydroxybenzotriazole (Scheme 1).…”

Presenting a Special Issue on “Medicinal Chemistry: From Targets to Therapies”

“…Thirty-three Letters, two Viewpoints, three Innovations and three Patent Highlights have been contributed by prominent players in their respective fields. Letters cover subjects such as cyclooxygenase 1 detection (by Malerba et al), FAK-targeting PROTACs (Gao et al), a chimeric inhibitor of macrophage migration inhibitory factor (Cirillo et al), Bruton’s tyrosine kinase (BTK) inhibitors (Zhang et al), oximes for acetylcholine esterase reactivation (Gambino et al), Zika virus inhibitors (Coluccia et al), phosphodiesterase 4B (PDE4B) inhibitors (Vadukoot et al), sirtuin 1–3 inhibition (Rajabi et al), analogs of the Gram-negative antibiotic zafirlukast (Howard et al), screens for hepatitis B (HBV) antiviral discovery (Hartman et al), A 3 adenosine receptor (A 3 AR) agonists (Tosh et al), fibroblast growth factor receptor 4 (FGFR4) inhibitors (Liu et al), inactivators of γ-aminobutyric acid aminotransferase (GABA-AT) (Shen et al), bitopic agonists of dopamine D 3 R (Battiti et al), harmaline analogs as COX-2 inhibitors (Uddin et al), imaging approaches in osteoarthritis (Uddin et al), HIV-1 protease inhibitors (Ghosh et al), brain-permeable tafamidis analogs (Sinha et al), melanocortin receptor antagonists (Ericson et al), choline antimetabolites (Bollenbach et al), bromodomain and extra-terminal (BET) inhibitors (Altenburg et al), raltegravir photoaffinity labels (Pala et al), selective orexin-1 antagonists (Préville et al), folate receptor targeting agents (Jin et al), intracellular peptide delivery (Ng et al), gibberellin-based inhibitors of NF-kB (Annand et al), agonists of a cannabinoid-activated GPCR (Schoeder et al), ceramide galactosyltransferase enzyme inhibitors (Thurairatnam et al), thermoresponsive perfluorocarbon hydrogels (Herneisey et al), a sigma-2 receptor agonist that could be effective in COVID-19 (Colabufo et al), a uric acid uptake inhibitor (Uda et al), and cationic photosensitizers (Mazumdar et al) . A Featured Letter describes the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that can serve both as a tool compound as well as a lead structure for apoptosis-inducing anticancer drugs (Wang et al) …”