TY - JOUR
T1 - Modulation of NRF2/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies
AU - Alzain, Abdulrahim A.
AU - Mukhtar, Rua M.
AU - Abdelmoniem, Nihal
AU - Shoaib, Tagyedeen H.
AU - Osman, Wadah
AU - Alsulaimany, Marwa
AU - Aljohani, Ahmed K.B.
AU - Almadani, Sara A.
AU - Alsaadi, Baiaan H.
AU - Althubyani, Maryam M.
AU - Mohamed, Shaimaa G.A.
AU - Mohamed, Gamal A.
AU - Ibrahim, Sabrin R.M.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/8
Y1 - 2023/8
N2 - Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand–residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand–protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies.
AB - Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand–residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand–protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies.
KW - ADME
KW - NRF2/KEAP1
KW - cancer
KW - drug discovery
KW - health and wellbeing
KW - molecular docking
KW - molecular dynamics
KW - natural compounds
KW - oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85168729891&partnerID=8YFLogxK
U2 - 10.3390/molecules28166003
DO - 10.3390/molecules28166003
M3 - Article
C2 - 37630254
AN - SCOPUS:85168729891
SN - 1420-3049
VL - 28
JO - Molecules
JF - Molecules
IS - 16
M1 - 6003
ER -