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*

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

doi:10.3389/fphar.2023.1281045

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*

Front Pharmacol. 2023 Oct 31:14:1281045. doi: 10.3389/fphar.2023.1281045. eCollection 2023.

Authors

Miriam Díaz-Rojas¹, Martin González-Andrade², Rodrigo Aguayo-Ortiz¹, Rogelio Rodríguez-Sotres¹, Araceli Pérez-Vásquez¹, Abraham Madariaga-Mazón³, Rachel Mata¹

Affiliations

¹ Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico.
² Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
³ Instituto de Química Unidad Mérida and Instituto de Investigaciones en Matemáticas Aplicadas y en Sistemas Unidad Mérida, Universidad Nacional Autónoma de México, Mexico City, Mexico.

Abstract

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 IC₅₀ values to ursolic acid (UA) (positive control, IC₅₀ = 26.5) were considered hits. These compounds were canophyllol (1), 5-O-(β-D-glucopyranosyl)-7-methoxy-3',4'-dihydroxy-4-phenylcoumarin (2), 3,4-dimethoxy-2,5-phenanthrenediol (3), masticadienonic acid (4), 4',5,6-trihydroxy-3',7-dimethoxyflavone (5), E/Z vermelhotin (6), tajixanthone hydrate (7), quercetin-3-O-(6″-benzoyl)-β-D-galactoside (8), lichexanthone (9), melianodiol (10), and confusarin (11). According to the double-reciprocal plots, 1 was a non-competitive inhibitor, 3 a mixed-type, and 6 competitive. The chemical space analysis of the hits (IC₅₀ < 100 μM) and compounds possessing activity (IC₅₀ 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 3, 5, 6, 7, 8, 9, and 11. Canophyllol (1), on the other hand, is a true analog of UA since it is an SAR continuous zone of the SAS map.

Keywords: E/Z vermelhotin; PTP1B; canophyllol; chemical space; scaffold hops.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from DGAPA-UNAM (PAPIIT-IN203523; PAPIIT-IN203222; PAPIIT-IN217320); CONAHCYT A1_S_11226 (CY011226); DGTIC-UNAM (LANCAD-UNAM-DGTIC-313 and LANCAD-UNAM-DGTIC-218); PAIP-5000-9140 from FQ-UNAM; and the Research Division of the Medical School, UNAM. MD-R acknowledges a fellowship from CONAHCYT (604010).