Demonstrating the Absence of Correlation Between Molecular Docking and in vitro Cytotoxicity in Anti-Breast Cancer Research: Root Causes and Practical Resolutions
Abstract
Introduction In silico methods have significantly transformed the landscape of drug discovery by enabling rapid and cost-effective screening of prospective therapeutic compounds. However, these computational techniques remain limited in their ability to fully predict complex biological behavior, particularly within the constraints of quantum level interactions and simplified receptor-ligand models. As such, validation through experimental data remains critical. Purpose This review aims to critically evaluate the correlation between molecular docking predictions specifically Gibbs free energy (ΔG) and in vitro cytotoxicity data (IC50 values) obtained from MCF-7 breast cancer cell studies. Methodology A structured methodology was employed, applying predefined inclusion and exclusion criteria to identify studies reporting both in silico molecular docking results and in vitro cytotoxicity data on the MCF-7 cell line, with a focus on compounds targeting breast cancer–related proteins. Results Findings demonstrated that, contrary to theoretical expectations, no consistent linear correlation was observed between ΔG values and IC50 across the analyzed compounds and targets. This discrepancy arises from several intertwined factors, including variability in protein expression within cell-based systems, compound-specific characteristics such as permeability and metabolic stability, and methodological limitations of docking approaches that rely on rigid receptor conformations and…
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