Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

Abstract

The use of computer-aided drug design (CADD) for the identification of lead compounds in radiotracer development is steadily increasing. Traditional CADD methods, such as structure-based and ligand-based virtual screening and optimization, have been successfully utilized in many drug discovery programs and are highlighted throughout this review. First, we discuss the use of virtual screening for hit identification at the beginning of drug discovery programs. This is followed by an analysis of how the hits derived from virtual screening can be filtered and culled to highly probable candidates to test in in vitro assays. We then illustrate how CADD can be used to optimize the potency of experimentally validated hit compounds from virtual screening for use in positron emission tomography (PET). Finally, we conclude with a survey of the newest techniques in CADD employing machine learning (ML).

Development and Optimization of 11C-Labeled Radiotracers: A Review of the Modern Quality Control Design Process

“…An effective radiotracer should have the following properties: 1) high affinity for the target of interest 2) low background binding or noise 3), and acceptable pharmacokinetic properties to be used in vivo. 55 There are several physiochemical properties that might be indicative of a promising compound to radiolabel for a potential novel radiotracer such as lipophilicity (expressed as log P oct/water ). log P oct/water values can be indicative of how the 11 C-compound might be absorbed by a biological system or organ from the bloodstream.…”

“…35 Computational chemistry has also become a popular screening tool to identify not only potential drugs but also radiotracers. 55 In Table 2, characterization techniques for novel radiotracers are listed along with how radiotracer viability was tested. Additionally, if it was discussed in the publication, the rationale behind the development of the PET tracer was included with the intended target.…”

“…log P oct/water values can be indicative of how the 11 C-compound might be absorbed by a biological system or organ from the bloodstream . Computational chemistry has also become a popular screening tool to identify not only potential drugs but also radiotracers …”

“…Ligand-based CADD is a pattern recognition technique that focuses on learning relationships between physiochemical properties in candidate radiotracers and a particular experimental value of interest such as binding affinity to the target. Ligand-based approaches work best when there are already a couple of known radiotracers with moderate effectiveness to assesss for similarities …”

Computer-Assisted Design of Peptide-Based Radiotracers

“…It can play an essential role in developing therapeutically important molecules, and it is considered very useful, at least for preclinical application and in the drug design phase [ 4 , 5 , 6 ]. CADD approaches offer insights into protein–ligand binding interactions and important chemical properties to lead to the identification and development of high-affinity radioligands [ 7 ].…”