Objective Bouchardatine (1) is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca, acting as a modulator of adipogenesis and lipogenesis, and as an anticancer agent. The natural product functions as an activator of proteins adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). We used molecular modeling to investigate the SIRT1-binding capacity of compound 1 and various structural analogues, such as orirenierine A (2) and orirenierine B (3) isolated from the medicinal plant Oricia renieri. Methods We investigated the binding to human SIRT1 (hSIRT1) of 25 natural products including the β-indoloquinazoline alkaloids 1 − 3 and analogues, in comparison with the reference product sirtinol (R and S isomers). A sirtinol binding model was elaborated starting from the closed and open state conformations of the catalytic domain of hSIRT1 (PDB structures 4KXQ and 4IG9). For each compound bound to SIRT1, the empirical energy of interaction (ΔE) was calculated and compared to that of sirtinol. Results In our model, compound 1 was found to bind modestly to the sirtinol site of SIRT1. In contrast, the presence of a phenolic OH group at position 7 on the quinazolinone moiety conferred a much higher binding capacity. Compound 2 provided SIRT1 protein complexes as stable as those observed with sirtinol. The replacement of the hydroxy substituent (2) with a methoxy group (3) reduced the SIRT1 binding capacity. Other SIRT1-binding natural products were identified, such as the alkaloids orisuaveolines A and B. Structure-binding relationships were discussed. Conclusion The study underlines the capacity of β-indoloquinazoline alkaloids to interact with SIRT1. This deacetylase enzyme could represent a molecular target for the alkaloid 2. This compound merits further attention for the design of drugs active against SIRT1-dependent pathologies.

Objective The mangrove tree Xylocarpus granatum J. Koenig (X. granatum) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-δ-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers. Methods We investigated the binding of the 18 xylogranatins to GSK-3β using molecular docking in comparison with two known reference GSK-3β ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3β, the empirical energy of interaction (ΔE) was calculated and compared to that obtained with known GSK-3β inhibitors and limonoid triterpenes that target this enzyme. Results Five compounds were identified as potential GSK-3β binders, Xyl-A, -C, -J, -N, and -O, for which the calculated empirical ΔE was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3β positions the furyl-δ-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3β binding. Structure-binding relationships are discussed. Conclusion GSK-3β may contribute to the anticancer effects of X. granatum extract. This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3β modulators.