Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics
6 affiliations
- 1Department of Pharmaceutical and Medicinal Chemistry, College of Pharmacy
- 2Afe Babalola University
- 3Research Laboratory for Rational Design of Drugs and Biomaterials (ResLaR
- 4Department of Biochemistry
- 5University of Nigeria
- 6Department of Life and Consumer Sciences, University of South Africa, Calabash Building, Johannesburg, South Africa
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.
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BibTeX
@misc{oluyemi2026optimizing,
title = {{Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics}},
author = {Wande M. Oluyemi and Shadrach C. Eze and Stephen C. Nnemolisa and Adewumi T. Adeniyi and Salerwe Mosebi and Innocent I. Okagu},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009348/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009348/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics
AU - Wande M. Oluyemi
AU - Shadrach C. Eze
AU - Stephen C. Nnemolisa
AU - Adewumi T. Adeniyi
AU - Salerwe Mosebi
AU - Innocent I. Okagu
PY - 2026
DA - 2026/09/23
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009348/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009348/v1
AB - 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.
ER -