AUTHOR=Díaz-Rojas Miriam , González-Andrade Martin , Aguayo-Ortiz Rodrigo , Rodríguez-Sotres Rogelio , Pérez-Vásquez Araceli , Madariaga-Mazón Abraham , Mata Rachel 

TITLE=Discovery of inhibitors of protein tyrosine phosphatase 1B contained in a natural products library from Mexican medicinal plants and fungi using a combination of enzymatic and in silico methods**

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1281045

DOI=10.3389/fphar.2023.1281045

ISSN=1663-9812

ABSTRACT=<p>This work aimed to discover protein tyrosine phosphatase 1B (PTP1B) inhibitors from a small molecule library of natural products (NPs) derived from selected Mexican medicinal plants and fungi to find new hits for developing antidiabetic drugs. The products showing similar IC<sub>50</sub> values to ursolic acid (UA) (positive control, IC<sub>50</sub> = 26.5) were considered hits. These compounds were canophyllol (<bold>1</bold>), 5-<italic>O</italic>-(β-D-glucopyranosyl)-7-methoxy-3′,4′-dihydroxy-4-phenylcoumarin (<bold>2</bold>), 3,4-dimethoxy-2,5-phenanthrenediol (<bold>3</bold>), masticadienonic acid (<bold>4</bold>), 4′,5,6-trihydroxy-3′,7-dimethoxyflavone (<bold>5</bold>), <italic>E</italic>/<italic>Z</italic> vermelhotin (<bold>6</bold>), tajixanthone hydrate (<bold>7</bold>), quercetin-3-<italic>O</italic>-(6″-benzoyl)-β-D-galactoside (<bold>8</bold>), lichexanthone (<bold>9</bold>), melianodiol (<bold>10</bold>), and confusarin (<bold>11</bold>). According to the double-reciprocal plots, <bold>1</bold> was a non-competitive inhibitor, <bold>3</bold> a mixed-type, and <bold>6</bold> competitive. The chemical space analysis of the hits (IC<sub>50</sub> &lt; 100 μM) and compounds possessing activity (IC<sub>50</sub> in the range of 100–1,000 μM) with the BIOFACQUIM library indicated that the active molecules are chemically diverse, covering most of the known Mexican NPs’ chemical space. Finally, a structure–activity similarity (SAS) map was built using the Tanimoto similarity index and PTP1B absolute inhibitory activity, which allows the identification of seven scaffold hops, namely, compounds <bold>3</bold>, <bold>5</bold>, <bold>6</bold>, <bold>7</bold>, <bold>8</bold>, <bold>9</bold>, and <bold>11</bold>. Canophyllol (<bold>1</bold>), on the other hand, is a true analog of UA since it is an SAR continuous zone of the SAS map.</p>