Search

[Display omitted] • A hybrid computational approach consisting of different computational methods is used. • Molecular electronic structures, and therapeutic potential of piperidine compounds are tested against SARS-CoV-2. • The molecular docking and MD simulations results reveal the significant therapeutic potential of designed compounds. • The MMPBSA analysis indicate that all the complexes possess good binding free energy at binding site of receptor. • ADMET analysis reveals that all eight ligands are efficient drug candidates for Mpro of SARS-CoV-2. In the current study, a hybrid computational approach consisting of different computational methods to explore the molecular electronic structures, bioactivity and therapeutic potential of piperidine compounds against SARS-CoV-2. The quantum chemical methods are used to study electronic structures of designed derivatives, molecular docking methods are used to see the most potential docking interactions for main protease (MPro) of SARS-CoV-2 while molecular dynamic and MMPBSA analyses are performed in bulk water solvation process to mimic real protein like aqueous environment and effectiveness of docked complexes. We designed and optimized piperidine derivatives from experimentally known precursor using quantum chemical methods. The UV–Visible, IR, molecular orbitals, molecular electrostatic plots, and global chemical reactivity descriptors are carried out which illustrate that the designed compounds are kinetically stable and reactive. The results of MD simulations and binding free energy revealed that all the complex systems possess adequate dynamic stability, and flexibility based on their RMSD, RMSF, radius of gyration, and hydrogen bond analysis. The computed net binding free energy (Δ G b i n d ) as calculated by MMPBSA method for the complexes showed the values of −4.29 kcal.mol−1 for P1, −5.52 kcal.mol−1 for P2, −6.12 kcal.mol−1 for P3, −6.35 kcal.mol−1 for P4, −5.19 kcal.mol−1 for P5, 3.09 kcal.mol−1 for P6, −6.78 kcal.mol−1 for P7, and −6.29 kcal.mol−1 for P8.The ADMET analysis further confirmed that none of among the designed ligands violates the Lipinski rule of five (RO5). The current comprehensive investigation predicts that all our designed compounds are recommended as prospective therapeutic drugs against Mpro of SARS-CoV-2 and it provokes the scientific community to further perform their in-vitro analysis. [ABSTRACT FROM AUTHOR]

[Display omitted] • A triple hybrid computational methodology is used to study modafinil drug derivatives. • Molecular docking was performed with ERα receptor to see potential interactions. • The complexes were further studied molecular dynamics simulations (120 ns). • The MMPBSA binding free energies were also calculated. • Structure-property relationship of compounds were predicted. Breast cancer (Bc a) 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 Bc a. 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 Bc a. 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), R g (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 (Δ G b i n d ) 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. [ABSTRACT FROM AUTHOR]