Molecular Docking and Antibacterial Activity of Sesterterpenoids From <i>Hyrtios Erectus</i>

The search for new antibiotics remains urgent due to the continuous evolution of microbes and their resistance to currently available antibiotics. The organic extract of a specimen of the Red Sea sponge Hyrtios erectus collected off Jeddah coast was subjected to sequential chromatographic fractionation. Three sesterterpenoids (1–3) along with an indole alkaloid (4) were isolated from H. erectus. Structure elucidation of the isolated was accomplished using NMR, UV, and IR spectroscopy along with MS spectrometry. The antibacterial activity of the isolated sesterterpenoids (1–3) was assessed against a set of Gram-positive and negative pathogens. Moreover, the hypothetical molecular docking studies of compounds 1–3 were motivated to evaluate their potential as bioactive compounds. Inspired by the docking results, scalarinol (1) exhibited the strongest binding affinity (S = –4.5829 kcal/mol), forming multiple interactions, including H-bonds (H-donor, H-acceptor) and H-pi stacking interactions with key residues (Ser389, Trp387, Tyr369). Heteronemin (2) showed moderate binding (S = –4.4790 kcal/mol), interacting over an H-acceptor bond with Gly391, while 12-O-deacetyl-19-deoxyscalarin (3) showed the weakest affinity (S = –4.3261 kcal/mol), engaging in an H-pi interaction with Tyr369. So, the findings recommend that, 1 had the highest potential as a bioactive natural component owing to its strong affinity with multiple binding modes. Furthermore, compounds 1–3 were subjected to the SwissADME program to discover of their physicochemical and pharmacokinetic properties influencing their drug-likeness. All compounds exhibited poor solubility with high gastrointestinal absorption and a single Lipinski violation, proposing moderate bioavailability Score (0.55). While both 1 and 2 exhibited non-BBB permeants and P-glycoprotein substrates, whereas 3 showed BBB permeability, no Pgp-substrate activity, Lipophilicity ranged from 3.51 to 3.83, and highest H-bond acceptors (6) over polar surface area (TPSA = 82.06) for 2. Compounds 1–3 showed good antibacterial activity against all examined positive and negative Gram pathogens with a noticeable performance of compound 1 with inhibition diameters (mm) ranging from 14.0 ± 1.22 to 20.1 ± 1.40 and 21.0 ± 2.21 to 16.1 ± 1.80, respectively. The recorded activity of compound 1 indicated its potential as a lead natural compound for future drug progress. Future research should confirm these findings using in vitro and in vivo trials.