TY - JOUR
T1 - Identification of phytomolecules as isoform and mutation specific PI3K-α inhibitor for protection against breast cancer using e-pharmacophore modeling and molecular dynamics simulations
AU - Mili, Ajay
AU - Birangal, Sumit
AU - Giridhar, Jyothi
AU - Nandakumar, Krishnadas
AU - Lobo, Richard
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - PI3K-α mutation plays a critical role in cancer development, notably in breast cancer, particularly within HR + /HER2- subtypes. These mutations drive tumor growth and survival by activating the PI3K/AKT/mTOR pathway, which is essential for cell proliferation and survival. Our research aimed to identify natural compounds that can inhibit mutant and specific isoforms of PI3K-α to prevent tumor progression. e-Pharmacophore model was generated using Receptor-Ligand complex using the Inavolisib drug (PDB:8EXV) and phase screening was performed using the Molport database of natural compounds. Through molecular docking studies we identified seven promising compounds for further molecular dynamics simulations. Among these, three compounds—STOCK1N-85097, STOCK1N-85998, and STOCK1N-86060—showed significant stability and interaction with PI3K-α. These compounds demonstrated favorable results in several parameters, including RMSD, RMSF, Rg, SASA, PCA, FEL, and total energy evaluations. Therefore, these compounds are projected to function as PI3K-α inhibitors and because of its natural origin it can possess fewer side effects than the conventional medicine, which should be validated by proper in vivo and in vitro models.
AB - PI3K-α mutation plays a critical role in cancer development, notably in breast cancer, particularly within HR + /HER2- subtypes. These mutations drive tumor growth and survival by activating the PI3K/AKT/mTOR pathway, which is essential for cell proliferation and survival. Our research aimed to identify natural compounds that can inhibit mutant and specific isoforms of PI3K-α to prevent tumor progression. e-Pharmacophore model was generated using Receptor-Ligand complex using the Inavolisib drug (PDB:8EXV) and phase screening was performed using the Molport database of natural compounds. Through molecular docking studies we identified seven promising compounds for further molecular dynamics simulations. Among these, three compounds—STOCK1N-85097, STOCK1N-85998, and STOCK1N-86060—showed significant stability and interaction with PI3K-α. These compounds demonstrated favorable results in several parameters, including RMSD, RMSF, Rg, SASA, PCA, FEL, and total energy evaluations. Therefore, these compounds are projected to function as PI3K-α inhibitors and because of its natural origin it can possess fewer side effects than the conventional medicine, which should be validated by proper in vivo and in vitro models.
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U2 - 10.1186/s13065-024-01317-w
DO - 10.1186/s13065-024-01317-w
M3 - Article
AN - SCOPUS:85212430850
SN - 2661-801X
VL - 18
JO - BMC Chemistry
JF - BMC Chemistry
IS - 1
M1 - 241
ER -