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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Virtual Screening–Derived Computational Lead Candidates for MAO-B Inhibition in Parkinson’s Disease: Pathway-Informed Docking, Molecular Dynamics, DFT and ADMET Evaluation

  • Ibrahim Khater1
  • Seifeldin Elabed2,3
  • Modather F. Hussein4
  • Khaled M. Alam-Eldein5
  • Ahmed A. Aly6
  • Somaia G. Hamada7
  • Ahmed T. Elhendawy8
8 affiliations
  1. 1Department of Biophysics, Faculty of Science, Cairo University, Giza 12613, Egypt
  2. 2Medical Biophysics Division, Physics Department, Faculty of Science, Helwan University, Cairo 11829, Egypt
  3. 3Biotechnology and Genetic Engineering Department, Faculty of Science, Helwan National University, Cairo 11829, Egypt
  4. 4Department of Chemistry, College of Science, Jouf University, Sakaka, Al-Jouf 72388, Saudi Arabia
  5. 5Molecular Biology and Biotechnology Department, School of Biotechnology, Badr University in Cairo, Badr City 11829, Egypt
  6. 6Unit of Scientific Research, Applied College, Qassim University, Buraydah 51452, Saudi Arabia
  7. 7Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
  8. 8Faculty of Engineering Technology, Elsewedy University of Technology–Polytechnic Egypt, Cairo 7060010, Egypt
Open at sourceDOICite

Abstract

Monoamine oxidase B (MAO-B) is a clinically validated target in Parkinson’s disease (PD), but docking rank alone is insufficient to establish a CNS-directed inhibitor. We integrated MAOB-related pathway context, domain-resolved structural annotation, GNINA virtual screening, predicted blood–brain barrier (BBB) permeation, molecular dynamics (MD), density functional theory (DFT) and ADMET assessment to nominate hypothesis-stage computational candidates. A pharmacophore-derived input collection 2870 entries was subjected to virtual screening; a curated BBB-positive, favorable Vina/CNN-affinity shortlist yielded PubChem CIDs 143667968, 42876521 and 1232631. The three candidates had similar reported GNINA scores. In single 100 ns MD trajectories, CID 42876521 displayed frequent protein–ligand hydrogen bonds, whereas CID 143667968 displayed almost none and reduced aromatic-cage fluctuation. CID 143667968 also had the smallest gas-phase HOMO–LUMO gap. All three compounds carried predicted mutagenicity, carcinogenicity and hERG alerts. CID 42876521 is therefore prioritized for validation, CID 143667968 is retained as a complementary hypothesis and CID 1232631 as a backup scaffold. These results define a preliminary, multi-parameter prioritization framework.

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Cite

BibTeXRIS
BibTeX
@article{khater2026virtual,
  title = {{Virtual Screening–Derived Computational Lead Candidates for MAO-B Inhibition in Parkinson’s Disease: Pathway-Informed Docking, Molecular Dynamics, DFT and ADMET Evaluation}},
  author = {Ibrahim Khater and Seifeldin Elabed and Modather F. Hussein and Khaled M. Alam-Eldein and Ahmed A. Aly and Somaia G. Hamada and Ahmed T. Elhendawy},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219781},
  url = {https://www.mdpi.com/1422-0067/27/21/9781},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Virtual Screening–Derived Computational Lead Candidates for MAO-B Inhibition in Parkinson’s Disease: Pathway-Informed Docking, Molecular Dynamics, DFT and ADMET Evaluation
AU  - Ibrahim Khater
AU  - Seifeldin Elabed
AU  - Modather F. Hussein
AU  - Khaled M. Alam-Eldein
AU  - Ahmed A. Aly
AU  - Somaia G. Hamada
AU  - Ahmed T. Elhendawy
PY  - 2026
DA  - 2026/10/30
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219781
UR  - https://www.mdpi.com/1422-0067/27/21/9781
AB  - Monoamine oxidase B (MAO-B) is a clinically validated target in Parkinson’s disease (PD), but docking rank alone is insufficient to establish a CNS-directed inhibitor. We integrated MAOB-related pathway context, domain-resolved structural annotation, GNINA virtual screening, predicted blood–brain barrier (BBB) permeation, molecular dynamics (MD), density functional theory (DFT) and ADMET assessment to nominate hypothesis-stage computational candidates. A pharmacophore-derived input collection 2870 entries was subjected to virtual screening; a curated BBB-positive, favorable Vina/CNN-affinity shortlist yielded PubChem CIDs 143667968, 42876521 and 1232631. The three candidates had similar reported GNINA scores. In single 100 ns MD trajectories, CID 42876521 displayed frequent protein–ligand hydrogen bonds, whereas CID 143667968 displayed almost none and reduced aromatic-cage fluctuation. CID 143667968 also had the smallest gas-phase HOMO–LUMO gap. All three compounds carried predicted mutagenicity, carcinogenicity and hERG alerts. CID 42876521 is therefore prioritized for validation, CID 143667968 is retained as a complementary hypothesis and CID 1232631 as a backup scaffold. These results define a preliminary, multi-parameter prioritization framework.
SN  - 1422-0067
ER  -