Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

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)

Identification of a nanomolar affinity a-synuclein fibril imaging probe by ultra-high throughput: In silico screening

Small molecules that bind with high affinity and specificity to fibrils of the a-synuclein (aS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple molecules with nanomolar affinity for aS fibrils and moderate specificity for aS over Aß fibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to aS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified molecule. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging molecular targets