Mitsue Oka, Mala Hikmawan Primana, Bonifacius Ivan Wiranata, Enade Perdana Istyastono, Florentinus Dika Octa Riswanto
Objective: This study aimed to investigate the allosteric binding site and dynamic stability of the sulforaphane-BACE1 complex to provide structural insights into its selective inhibition mechanism. Methods: Molecular docking was performed using YASARA Structure, followed by five independent 10 ns molecular dynamics simulations conducted with GROMACS to evaluate the stability of the sulforaphane–BACE1 complex. Key interactions and stability parameters were analyzed using RMSD-based metrics and interaction fingerprint profiling. Results: Global docking identified 35 possible binding pockets, with one predominant allosteric site showing the most favorable binding energy and clustering. Molecular dynamics simulations revealed that sulforaphane maintained stable orientations in two of five trajectories (R2 and R4), indicating replica-dependent stability consistent with moderate affinity and allosteric flexibility. Interaction analysis highlighted persistent hydrophobic contacts with ALA173, LEU172, PRO313, GLU315, and ASP323 as major stabilizing residues. Conclusion: Sulforaphane demonstrates moderate but reproducible allosteric binding to BACE1, primarily stabilized by hydrophobic interactions and key polar contacts. These findings establish a structural model supporting sulforaphane’s selective modulation of BACE1 and provide a computational framework for designing improved allosteric inhibitors for Alzheimer’s disease therapy. © 2026 The Authors. Published by Innovare Academic Sciences Pvt Ltd.
Magister of Pharmacy Study Program, Faculty of Pharmacy, Sanata Dharma University, Campus 3 Paingan, Maguwoharjo, Depok, Sleman, Yogyakarta, 55282, Indonesia; Pharmaceutical Sciences Department, Faculty of Pharmacy, Widya Mandala Catholic University, Surabaya, Indonesia; Research Center for Cheminformatics and Molecular Modeling, Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jl. Pluit Raya No. 2, Jakarta Utara, DKI Jakarta, 14440, Indonesia; Research Group of Computer-Aided Drug Design and Discovery of Bioactive Natural Products, Sanata Dharma University, Yogyakarta, 55282, Indonesia