Natural Compound Modulates the Cervical Cancer Microenvironment—A Pharmacophore Guided Molecular Modelling Approaches

Abstract

Cervical cancer is regarded as one of the major burdens noticed in women next to breast cancer. Although, human papilloma viruses (HPVs) are regarded as the principal causative agents, they require certain other factors such as oestrogen hormone to induce cervical cancer. Aromatase is an enzyme that converts androgens into oestrogens and hindering this enzyme could subsequently hamper the formation of oestrogen thereby alleviating the disease. Accordingly, in the current investigation, a structure based pharmacophore was generated considering two proteins bearing the Protein Data Bank (PDB) codes 3EQM (pharm 1) and 3S7S (pharm 2), respectively. The two models were employed as the 3D query to screen the in-house built natural compounds database. The obtained 51 compounds were escalated to molecular docking studies to decipher on the binding affinities and to predict the quintessential binding modes which were affirmed by molecular dynamics (MD) simulations. The compound has induced dose-dependent down regulation of PP2B, Nitric oxide synthase-2 (NOS2), and Interleukin 6 (IL-6) genes in the HeLa cells and has modulated the expression of apoptotic genes such as Bax, Bcl2, and caspases-3 at different concentrations. These results guide us to comprehend that the identified aromatase inhibitor was effective against the cervical cancer cells and additionally could server as scaffolds in designing new drugs.

Thalassosterol, a New Cytotoxic Aromatase Inhibitor Ergosterol Derivative from the Red Sea Seagrass Thalassodendron ciliatum

“…The binding interaction shows that the steroidal nucleus, overlapped with the hydrophobic environment of the binding pocket with ring D, is oriented towards the Met 374 residue and the β -face positioned towards the heme moiety. It can be clearly noticed that, while the hydroxy group of the ring A engages one hydrogen bond donor with the backbone amide of Met 374 as reported (3.82 Å) [ 42 ], the C15-keto oxygen atom of ring D acts as a hydrogen bond acceptor from Arg 115 (3.12 Å). Moreover, three extra hydrogen bond donors were involved via the interaction with Cys 417 residue with binding interaction score −8.219 kcal/mol ( Figure 6 ).…”

Discovery of Lonafarnib-Like Compounds: Pharmacophore Modeling and Molecular Dynamics Studies

“…Molecular dynamics simulation studies were launched to elucidate the dynamic behavior of small molecules at protein active sites and were conducted as described earlier. , In order to accomplish this, the GROMACS v5.0.6 package was employed with the CHARMm 27 force field obtaining the ligand topologies from SwissParam . A double level equilibration was conducted by utilizing a constant number of particles, volume, and temperature (NVT) and constant number of particles, pressure, and temperature (NPT), executed for 1 ns each with a V-rescale thermostat and Parrinello–Rahman barostat, correspondingly.…”

Design, synthesis, spectral analysis and molecular docking studies of some cyclic imide as potential anti breast and cervical cancer agents

“…Raw proteins from protein data bank with PDB (3pp0) and (3EQM) named Human estrogen receptor is further prepared for docking studies by removing all water molecules and the H atoms and followed by subsequent energy minimization using the AutoDock Vina and Discovery Studio 2017 R2 Client [27][28][29][30].…”

“…Molecular docking procedure was carried out using the AutoDock Tools 4.0 (version: 1.5.6) program docking between Human estrogen receptors (PDB ID:3PP0) and (PDB ID: 3PP0) as a targets and optimize prepared cyclic imide derivatives (a1-a4) as a ligands. Automated dockings were carried out to calculated binding energy and locate the convenient binding orientations and conformations of prepared cyclic imide derivatives as a ligands in the Human estrogen receptor binding pocket by AutoDock Vina [27].…”