Potential Aromatase Inhibitors from Centella asiatica with Non-synonymous SNP_S - A Computational Approach

Aromatase inhibitors are used in the treatment of breast cancer as they are effective in decreasing the concentration of estrogen. As SNPs impact the efficacy or toxicity of drugs, evaluating them with mutated conformations would help in identifying potential inhibitors. In recent years, phytocompounds have been under scrutiny for their activity as potential inhibitors.

In this study, we have evaluated Centella asiatica compounds for their activity on aromatase with clinically significant SNPs: rs700519, rs78310315 and rs56658716.

Using AMDock v.1.5.2, which uses the AutoDock Vina engine, molecular docking simulations were carried out, and the docked complexes were analyzed for their chemical interactions such as polar contacts using PyMol v2.5. The mutated conformations of the protein and force field energy differences were computationally derived using SwissPDB Viewer. PubChem, dbSNP and ClinVar databases were used to retrieve the compounds and SNPs. ADMET prediction profile was generated using admetSAR v1.0.

Docking simulations of the C. asiatica compounds with the native and mutated conformations showed that out of the obtained fourteen phytocompounds, Isoquercetin, Quercetin and 9H-Fluorene-2-carboxylic acid were able to dock with best scores in terms of binding affinity (- 8.4kcal/mol), Estimated Ki (0.6 μM) values and Polar Contacts in both native and mutated conformations (3EQM, 5JKW, 3S7S).

Our computational analyses predict that the deleterious SNPs did not impact the molecular interactions of Isoquercetin, Quercetin and 9H-Fluorene-2-carboxylic acid, providing better lead compounds for further evaluation as potential aromatase inhibitors.