Identification of a Selective PDE4B Inhibitor From Bryophyllum pinnatum by Target Fishing Study and In Vitro Evaluation of Quercetin 3-O-α-L-Arabinopyranosyl-(1→2)-O-α-L-Rhamnopyranoside

Abstract

Natural products are considered an important source of bioactive compounds especially in biodiversity-rich countries like Brazil. The identification of potential targets is crucial to the development of drugs from natural sources. In this context, in silico methodologies, such as inverse virtual screening (target fishing), are interesting tools as they are a rational and direct method that reduces costs and experimental time. Among the species of Brazilian biomes, Bryophyllum pinnatum (Lam.) Oken, native to Madagascar, is widely used by the population to treat inflammation conditions. It has a remarkable presence of flavonoids, including quercetin 3-O-a-L-arabinopyranosyl-(1!2)-O-a-Lrhamnopyranoside (1), considered one of its major compounds. However, until now there were no studies addressing its putative mechanism of action and explaining its pharmacological action. The enzyme PDE4B, known as an antiinflammatory protein, was indicated as a promising target by target fishing methods. This activity was confirmed by in vitro enzymatic inhibition, and an expressive selectivity of PDE4B over PDE4A was demonstrated. The interactions were investigated through molecular dynamics simulations. The results were pioneering, representing an advance in the investigation of the antiinflammatory action of B. pinnatum and confirm the potential of the flavonoid as a chemical extract marker. Also, the flavonoid was shown to be a promising lead for the design of other selective PDE4B blockers to treat inflammatory diseases.

The psychoactive effects of Bryophyllum pinnatum (Lam.) Oken leaves in young zebrafish

“…Among the natural compounds, flavonoids have been studied for their multi-target behavior in the CNS and have neuroprotective activity with different mechanisms of action [ 31 ]. Quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside ( 2 ), the major compound present in LBP, can be easily extracted using water [ 32 ]; however, the effects observed using the crude plant extract are not expected to be due to this compound alone, as the hydrolysis of a range of flavonol and isoflavone glycosides by the enzyme lactase phrorizin hydrolase, found in the small intestine of mammals, makes it difficult to absorb these compounds as a whole molecule [ 33 , 34 ]. Quercetin affects locomotion and induces deformities in ZF larvae exposed during development [ 35 ].…”

“…Stress response and inflammation are triggered to eliminate stressors, promote adaptations, and restore homeostasis in biological systems [ 53 ]. BP is used in traditional medicine as an anti-inflammatory agent [ 5 ], and quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside ( 2 ), the major compound, and bufadienolides have also been reported as anti-inflammatory compounds in previous studies [ 34 , 54 ]. Thus, it is possible to connect the ethnopharmacological synergy information of the crude extract with our results.…”

Identification of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

“…Initially conceived by Chen and Zhi [37] in the identi cation of targets, the IVS method has grown over the years, with several tools available for commercial and scienti c use being reported. Studies demonstrate the e ciency of the methodology when carrying out in vitro studies with the best pro le targets listed by the program [23,38]. Thus, it is observed that the IVS has been shown to be a powerful and robust tool in drug development.…”

Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

“…Finally, it should be noted that rolipram shows high affinity for PDE4B; however, it exhibits side-effects, such as emesis, due to the inhibition of the PDE4D subtype. Owing to their potential anti-inflammatory activity, there is an active search of novel and selective PDE4B inhibitors [ 19 , 51 ] which avoid these PDE4D-related side-effects. Although several candidates have been developed, they have neither been tested in chronic preclinical studies (except for inhaled administration against respiratory diseases) nor incorporated into clinical practice.…”