Marcus D Hanwell, et al;. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics,. (2012), 4:17.
Molecular Modeling and Docking Studies of Aromatase Inhibitors with Aromatase For ERP Breast Cancer
Aromatase induces cancer growth by stimulating estrogen synthesis in breast cancer tissue. Therefore, aromatase is a potential drug target for breast cancer treatment. Currently, two types of aromatase inhibitors, steroidal (e.g. Exemestane) and non-steroidal (e.g. Letrozole) are available as gold standard for the therapy. But, these existing therapeutics pose some major side-effects such as loss of bone mineral density (may lead to osteoporosis or bone fractures). Our In silico studies on Exemestane and Letrozole as well as their derivatives explored significant interaction with aromatase (PDB ID: 3S7S) to understand the molecular insights to overcome such side-effects. Molecular modeling and energy minimization of ligands (Exemestane, Letrozole and their derivatives) was carried out by Avogadro software till atomic stable conformation obtained. The Gasteiger charges were assigned to ligands as per standard protocol. Then, Exemestane, Letrozole and their derivatives were docked against receptor aromatase. Virtual Screening of docked ligands was carried out based on binding energy and number of hydrogen bonds and other intermolecular interactions. Docking studies of the compounds were performed with FlexX software. The docking rank was assigned to each ligand based on highest negative score with aromatase enzyme. Furthermore, the stability of the interactions made by the hit analogues with receptor aromatase was evaluated based on molecular dynamics simulation studies. Molecular dynamics (MD) and Simulation of aromatase were perform using Desmond (Schrödinger) software until stable conformation reached within the range of 100ns for both of them at suitable equilibrium. All the stable conformations for ligand trajectories were captured at equal time intervals. Screened ligands from docking may inhibit the Aromatase in cancer tissue under In vitro and In vivo experiments.
Aromatase
Estrogen
Ligand RMSD (Ǻ)
Exemestane
Exemestane
-21.5189
S_1
-25.901
S_16
-22.8183
S_19
-22.5551
S_21
-22.4035
S_22
-22.3364
Interacting amino-acid residue
Bond length (Ǻ)
Compound Name
Binding Affinity (kcal/mol)
Arg 115
2.53
Letrozole
-21.1135
Met 374
2.89
Arg 115
2.46
NS_8
-25.3044
Met 374
2.91
Met 374
2.49
NS_11
-25.0326
Arg 115
2.60
Arg 115
2.67
NS_14
-24.5864
Met 374
2.97
Arg 115
2.68
Met 374
2.95
NS_17
-24.1083
Met 374
2.49
Arg 115
2.60
NS_19
-23.9245
Non-Steroidal
Steroidal
Compound Name
Binding Energy (kcal/mol)
Interacting amino-acid residue Met 374 Arg 115 Ser 478 Ser 478 Met 374 Arg 115 Arg 115 Met 374 Ser 478 Met 374 Arg 115 Thr310 Ala 307 Met 374 Ser 478 Met 374
Bond length (Ǻ) 2.72 2.87 2.93 1.66 2.10 2.97 2.11 2.77 2.63 2.82 2.86 1.66 2.10 2.97 2.61 2.82
Letrozole
Conclusion
On the basis of molecular docking and Molecular Dynamics studies, top 5 each of steroidal and non steroidal lead molecules were screened from retrieved ligands according to their binding energy, no. of H- bonds made with the protein and bond distance. The compound S_1, with binding energy of -25.901 (as compared to the binding energy of 21.5189 of EXM) was found to be the best steroidal lead. Likewise, the compound NS_8, with binding energy of -25.3044 (as compared to the binding energy of -21.1135 of LTZ) was found to be the best nonsteroidal lead. On performing molecular dynamics simulation study for 100ns, we found out that the protein and ligand were equilibrated well till 50ns; which proves the stability of the protein-ligand binding. Further, clinical trials can be done to explore the effects of these Fig.1 Exemestane docked with Aromatase Fig.2 Letrozole docked with Aromatase molecules as no proven analysis of this have been obtained until now and a NOVEL DRUG can be synthesized.
References 1. Ghosh D. et al;. Novel Aromtase Inhibitors by Structure-guided design. Journal of Medicinal Chemistry, (2012), 55: 8464-8476. 2. Marcus D Hanwell, et al;. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, (2012), 4:17.
Acknowledgement Fig.3 S_1 docked with Aromatase
Fig.4 NS_8 docked with Aromatase
The authors are thankful to Dr. D.Y Patil Vidyapeeth, Pune for infrastructure facility, and DST-SERB, New Delhi (YSS/2015/002035) for computational assistance.
