Estrogenic Activity of Tetrazole Derivatives Bearing Bisphenol Structures: Computational Studies, Synthesis, and In Vitro Assessment

Publication: J Chem Inf Model
Software: ADMET Predictor®

Abstract

Abstract Image

The classification of bisphenol A (BPA) as an industrial endocrine disruptor has led to a ban of this ubiquitous critical starting material from food and medical applications. Thus, scientists worldwide are researching to develop non-ER binding starting compounds to fulfill unmet market needs. In line with this trending research topic, the current paper highlights the development of tetrazole derivatives bearing a bisphenol structure (TbB) as a novel weak binder or potential inactive to the estrogen receptor (ER) and androgen receptor (AR). The structure and ligand-based approach supported by binding affinity analysis, electrostatic complementarity, ADMET prediction, and in silico studies identified TbBs as privileged substitutes for BPA. Five TbB ligands were successfully synthesized and subjected to biological testing comprising radioligand competitive binding and functional cellular assays. The measured IC50 value for BPA was found to be 0.24 μM, whereas all the inhibitions were less than 15% for the two TbB ligands, 223-2 and 223-3. As these TbB ligands did not meet the established acceptance criteria of 50% inhibition, they are considered as extremely weak binders to ERα. Steric clashes, the desolvation effect, and the increased total polar surface area (TPSA) of TbB ligands in the hydrophobic binding site are hypothesized to be possible reasons for low binding. Modeling studies complemented by bioassays highlight TbB compounds as privileged prospective BPA replacements. However, more research on TbB ligand toxicity is needed to understand and substantiate that the adverse effects on the hormonal system, for example, via metabolic activation, are not elicited.

By Umesh B. Gadgoli, Sunil Kumar Y.C., Deepak Kumar, Ms. Maya Pai, Sravani Pulya, Balaram Ghosh, and Onkar Prakash Kulkarni