Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics
Year: 2026
Type: preprint
Abstract: Alliin (S-(2-propenyl)-L-cysteine sulfoxide) was initially identified as a potential inhibitor of BACE-1, with the ability to chelate the catalytic dyad, but with very poor pharmacokinetics. We aimed to optimize these pharmacokinetic parameters, with a possible gain in affinity by growing the ligand towards the sub-pocket of the active site under the flaps. We employed fragment growing, implemented in the ligand designer module of Schrodinger, to extend 2-propenyl-alliin (a derivative of alliin) from both ends, with the multiparameter optimization (MPO) score as a guide. Select hits were further validated using molecular dynamics simulations for 500ns in explicit water. Ligands C37, C47, and C57 showed MPO scores above 0.9 with great improvements in LogP ranging from 1.129 to 2.147 and MW from 358g/mol to 384g/mol compared to -0.421 and 225.35g/mol in 2-propenyl-alliin, respectively. All the derivatives maintained an iron-clad charged contacts with the aspartic dyad throughout the simulation; while C47 and C57 made π-π interactions with Phe112 under the flap, using their pyridine side chains. Global root mean square deviations (RMSD), ligand RMSD, and root mean square fluctuations showed very stable ligand-BACE-1 complexes. Binding free energies (BFE; kcal/mol), computed using the MMGBSA, were two-fold higher (in C47, -52.29 ± 5.56 kcal/mol and C57, -59.40 ± 4.66) than that of the verubecestat (-26.78± 3.91), or alliin (−33.82 ± 4.25) in the previously reported work. However, the ligand-bound BACE-1 maintained an open conformation (distance D0>13.0Å). We have utilized fragment growing and molecular dynamics to provide derivatives of cysteinyl sulfoxides with improved pharmacokinetics, hydrophobic contact with Phe112, and improved BFE, while maintaining interactions with the catalytic dyad of BACE-1.
Source: ChemRxiv
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214104385