Computerized Molecular Docking for the Computational Binding Efficiency of PET Radiotracers: A Comprehensive Workflow

Introduction: Computational Molecular Docking is a resource that has emerged from the advent of bioinformatics, enabling analysis of binding affinities through 3D protein structure modeling. Specifically, molecular docking software such as Autodock Vina, provide insights on chemical interactions underlying optimal conformation of a ligand into a protein’s active site. This has major applications in novel PET radiotracer synthesis, as molecular docking can be used for pharmaceutical screening of candidate tracers before retrosynthetic development. Understanding precise strengths and binding affinities is especially crucial to assess potential off-target binding interactions and permeability of membranes prior to in vivo radiotracer injection analysis.

Methods: A meticulous literature review was performed with insights from molecular docking applications in radiotracer synthesis. Inclusion of articles were selected from a broad range of PET imaging fields to provide scope of the docking’s application. Additionally, methodology of molecular docking, including its synergistic combination with 3D protein modeling software, were studied. This project aims to 1) present scientists with a potential tool that can aid in synthesis, 2) convey a wide range of past research that has utilized molecular docking, and 3) describe a comprehensive framework for implementation.

Results: A wide range of studies have utilized molecular docking, including researchers synthesizing 18F tracers binding to fibroblast activation proteins in brains, designing 68Ga inhibitors for poly ADP-ribose polymerase tumor targeting, and development of 18F monoacylglycerol lipase mapping PET tracers for neurological diseases. In these studies, molecular docking aided in identification of optimal ligand fitting, which were refined through techniques such as replacement of cyclopropyl ring substituents or insertion of moieties. Furthermore, molecular docking enables rapid quantification of π-π, hydrophobic, and h-bonding interactions, orientation of ligand insertion, and individual functional group effects on ligand binding. In the synthesis of multiple radiotracers for experimentation with small alterations in chemical structure, molecular docking simulations can save complex synthetic work. Applications of molecular docking provide a 3D view of structure in a comprehensive format and can be integrated into protein databases and Pymol modeling software for better analysis. In one such study, identification of the lowest energy conformation was associated with optimal orientation to the catalytic triad of the protein that would otherwise enable hydrolytic cleavage, which further supported binding affinity results from cellular uptake staining experiments. In another, the PET radiotracer 68Ga PSMA11 and therapeutic radiopharmaceutical (such as 177Lu PSMA617) are slightly different (PSMA11 versus PSMA617), this computational technique can be utilized to predict the kinetic of one from the imaging results.

A typical molecular docking workflow starts with x-ray crystallography with high probability of correct molecular structure. In the case of Autodock, proteins can be modified with AutoDockTools provided by the Scripps Research Institute. Next, binding map adjustments must be made, including docking grid box arrangements and parameters for docking. Lastly, automated docking will rank configurations and identity potential binding interactions.

Conclusions: Molecular docking software can provide important insights on radiotracer ligand binding prior to actual synthesis. Rapid analysis on binding interactions and active site configurations can aid in development of novel radiotracers.