Insighting the inhibitory potential of novel modafinil drug derivatives against estrogen alpha (ERα) of breast cancer through a triple hybrid computational methodology

Afsheen Saba, Fatima Sarwar, Shabbir Muhammad, Mubashar Ilyas, Javed Iqbal, Abdullah G. Al-Sehemi, Khurshid Ayub, Mazhar Amjad Gilani, Muhammad Adnan

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Breast cancer (Bca) is the prominent, most commonly detected, and the leading cause of mortality among women. Estrogen receptor alpha (ERα) is considered an important receptor for the proliferation of this disease and its blockage is necessary for the treatment of Bca. The purpose of the current study is to design novel potential inhibitors against ERα of Bca. We designed modafinil drug derivatives using quantum chemical methods. These newly designed derivatives were put under an in-silico investigation followed by molecular docking simulation, molecular dynamics simulation, and MMPBSA analysis to find novel inhibitors of ERα. Moreover, three reference anticancer drugs; tamoxifen, raloxifene, and toremifene are also studied against ERα of Bca. The spectroscopic and structural features of sulfoxide-based designed derivatives of modafinil drug M1 ((R)-2-(banzhydrylsulfinyl-N,N diethylacetamide) have been evaluated using different quantum chemical analyses. The findings of the current investigation demonstrate that all studied ligands exhibit the binding energy ranges (-5.3 to −5.8 Kcal/mol). The designed compounds showed effective hydrophobic (alkyl, π-alkyl, π-sigma, π-amide stacked, π-π T-shaped) interactions and hydrogen bond formation and are anticipated to be potential inhibitors against ERα. Additionally, designed derivatives have a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and drug-likeness properties obeying RO5 without any toxicity. The stability profile of designed derivatives (M1-M6) was further validated by molecular dynamics (MD) simulation and calculate binding free energy by the MM-PBSA approach. All ligand–protein complexes showed structural stability over the 120 ns MD simulation time. The MD simulation of the complex system was carried out by RMSD (root-mean-square deviation) of C α atoms of ERα, RMSF (root mean square fluctuations), Rg (radius of gyration), SASA (solvent accessible surface area), and dynamic behavior of hydrogen bonds. The MD simulation results illustrate that RMSD for trajectories of designed derivative complexes over 120 ns are within the acceptable deviation range of ∼ 3 Å. The calculations of net binding free energy (ΔGbind) between the designed derivatives and their complexes are found to be −8.50 Kcal/mol (M1) at maximum and −5.197 Kcal/mol (M3) at a minimum among all derivatives. The outcomes of our current in-silico investigation will evoke the scientific community to carry out further in vivo and in vitro studies on designed modafinil derivatives that can be potential therapeutic drug candidates against ERα.
Original languageEnglish (US)
Pages (from-to)120234
JournalJournal of Molecular Liquids
StatePublished - Sep 11 2022
Externally publishedYes

Bibliographical note

KAUST Repository Item: Exported on 2022-09-19
Acknowledgements: The authors from King Khalid University extend their appreciation to the Deanship of Scientific Research at King Khalid University of Saudi Arabia for supporting this research through grant number RGP.2/194/43. For computer time, this research used the resources of the Supercomputing Laboratory at King Abdullah University of Science & Technology (KAUST) in Thuwal, Saudi Arabia.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.

ASJC Scopus subject areas

  • Materials Chemistry
  • Spectroscopy
  • Atomic and Molecular Physics, and Optics
  • Physical and Theoretical Chemistry
  • Electronic, Optical and Magnetic Materials
  • Condensed Matter Physics


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