Structural and Energetic Insights into the Binding of L- and D-Arginine Analogs with Neuropilin-1 (NRP1): Molecular Docking, Molecular Dynamics and DFT Calculations.

Abstract

Neuropilin-1 (NRP1) is a transmembrane glycoprotein that binds numerous ligands, including vascular endothelial growth factor A (VEGFA) that stimulates blood vessel formation. Preclinical trials propose that NRP1 inhibition blocks neoplasm cell proliferation and slows tumor growth by suppressing angiogenesis. As such, VEGFA/NRP1 signaling is a potential target for carcinoma inhibition. Since arginine (Arg) regulates nutrient-responsive rapamycin signaling, which in turn regulates cell growth and metabolism, Arg, as well as simple structural variations of _L- and _D-Arg, were selected to study in-silico structural and energetic influences of such ligands on NRP1 signaling. Initially, AutoDock Vina1.1.2 software performance was assessed to predict binding modes of Arg analogs with NRP1 based on the available experimental data. Molecular docking and molecular dynamics (MD) simulations over 100 ns were run to inspect the potency of Arg analogs to bind with NRP1. Analog-NRP1 complex binding affinities (ΔG_binding) were evaluated using the MM/GBSA approach. Results indicated that _L-/_D-Agd- and _L-/_D-Agn-NRP1 complexes exhibited binding affinities greater than the co-crystallized _L-homoarginine ligand (calc.-31.2 kcal.mol^-1) with ΔG_binding values of -40.5/-40.6 and -40.0/-36.2 kcal.mol^-1, respectively. Structural and energetic analyses were performed to examine further _L-/_D-Agd and _L-/_D-Agn. Quantum mechanical calculations were performed to confirm the outcomes obtained from docking computations and MD simulations.