Bioconversion of biosynthetic heterocyclic compounds has been utilized to produce new semisynthetic pharmaceuticals and study the metabolites of bioactive drugs used systemically. In this investigation, the biotransformation of natural heterocyclic alkaloid papaverine via filamentous fungi was explored. Molecular docking simulations, using protein tyrosine phosphatase 1B (PTP1B), α-glucosidase and pancreatic lipase (PL) as target enzymes, were performed to investigate the antidiabetic potential of papaverine and its metabolites in silico. The metabolites were isolated from biotransformation of papaverine with Cunninghamella elegans NRRL 2310, Rhodotorula rubra NRRL y1592, Penicillium chrysogeneum ATCC 10002 and Cunninghamella blackesleeana NRRL 1369 via reduction, demethylation, N-oxidation, oxidation and hydroxylation reactions. Seven metabolites were isolated: namely, 3,4-dihydropapaverine (metabolite 1), papaveroline (metabolite 2), 7-demethyl papaverine (metabolite 3), 6,4'-didemethyl papaverine (metabolite 4), papaverine-3-ol (metabolite 5), papaverinol (metabolite 6) and papaverinol N-oxide (metabolite 7). The structural elucidation of the metabolites was investigated with 1D and 2D NMR and mass spectroscopy (EI and ESI). The molecular docking studies showed that metabolite 7 exhibited better binding interactions with the target enzymes PTP1B, α-glucosidase and PL than did papaverine. Furthermore, papaverinol-N-oxide (7) also displayed inhibition of α-glucosidase and lipase enzymes comparable to that of their ligands (acarbose and orlistat, respectively), as unveiled with an in silico ADMET profile, molecular docking and molecular dynamics studies. In conclusion, this study provides evidence for enhanced inhibition of PTP1B, α-glucosidase and PL via some papaverine fungal transformation products and, therefore, potentially better antidiabetic and antiobesity effects than those of papaverine and other known therapeutic agents.

中文翻译：

---

罂粟酚-N-氧化物：罂粟碱的一种微生物生物转化产物，具有潜在的抗糖尿病和抗肥胖活性，通过计算机筛选揭示。

生物合成杂环化合物的生物转化已被用于生产新的半合成药物和研究全身使用的生物活性药物的代谢物。在这项研究中，探索了天然杂环生物碱罂粟碱通过丝状真菌的生物转化。使用蛋白酪氨酸磷酸酶 1B (PTP1B)、α-葡萄糖苷酶和胰脂肪酶 (PL) 作为靶酶进行分子对接模拟，以研究罂粟碱及其代谢物在计算机中的抗糖尿病潜力。通过还原、去甲基化、N-氧化、氧化和羟基化反应，从罂粟碱与秀丽隐杆线虫 NRRL 2310、红酵母 NRRL y1592、产黄青霉 ATCC 10002 和黑杉 NRRL 1369 的生物转化中分离出代谢物。分离出七种代谢物：3,4-二氢罂粟碱（代谢物1）、罂粟碱（代谢物2）、7-去甲基罂粟碱（代谢物3）、6,4'-二去甲基罂粟碱（代谢物4）、罂粟碱-3-醇（代谢物 5）、罂粟酚（代谢物 6）和罂粟酚 N-氧化物（代谢物 7）。使用 1D 和 2D NMR 以及质谱（EI 和 ESI）研究了代谢物的结构解析。分子对接研究表明，代谢物 7 与靶酶 PTP1B、α-葡萄糖苷酶和 PL 的结合相互作用优于罂粟碱。此外，罂粟酚-N-氧化物 (7) 还显示出与其配体（分别为阿卡波糖和奥利司他）相当的 α-葡萄糖苷酶和脂肪酶抑制作用，如计算机 ADMET 图谱、分子对接和分子动力学研究所揭示的那样。综上所述，