Integrated Computational Modeling Reveals a Structurally Plausible Transient Paclitaxel–NK2R Interaction

Abstract

Background: Paclitaxel is a cornerstone chemotherapeutic agent widely used in breast cancer treatment, primarily through the stabilization of microtubule dynamics. Beyond its canonical tubulin-targeting activity, increasing evidence suggests that paclitaxel may engage additional molecular targets, contributing to its complex pharmacological profile. In this study, an integrated computational workflow was applied to evaluate the structural compatibility between paclitaxel and the neurokinin-2 receptor (NK2R), a G protein-coupled receptor involved in tumor-associated inflammatory and proliferative signaling pathways. Physicochemical profiling and target prediction were performed using SwissADME and SwissTargetPrediction, followed by molecular docking and molecular dynamics simulations using AutoDock Vina and GROMACS 2024.1. Paclitaxel exhibited physicochemical properties consistent with transient interactions in hydrophobic transmembrane environments. Docking analysis identified a plausible binding mode within the NK2R transmembrane cavity, primarily stabilized by hydrophobic contacts. Molecular dynamics simulations over 100 ns revealed stable ligand occupancy and overall complex stability, while MM-PBSA calculations indicated a favorable transient association. The predicted interaction is consistent with secondary or non-canonical receptor engagement. While NK2R is not established as a pharmacological target of paclitaxel, the results support the structural feasibility of a previously uncharacterized receptor interaction and provide a reproducible computational framework for exploring GPCR-associated effects of cytotoxic agents.