Identifying
ligand
binding sites on proteins is a critical step
in target-based drug discovery. Current approaches to this require
resource-intensive screening of large libraries of lead-like or fragment
molecules. Here, we describe an efficient and effective experimental
approach to mapping interaction sites using a set of halogenated compounds
expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites
identify productive drug-like interactions, which are identified sensitively
and unambiguously by X-ray crystallography, exploiting the anomalous
scattering of the halogen substituent. This mapping of protein interaction
surfaces provides an assessment of druggability and can identify efficient
start points for the de novo design of hit molecules incorporating
the interacting motifs. The approach is illustrated by mapping cyclin-dependent
kinase 2, which successfully identifies orthosteric and allosteric
sites. The hits were rapidly elaborated to develop efficient lead-like
molecules. Hence, the approach provides a new method of identifying
ligand sites, assessing tractability and discovering new leads.
We
report how the rearrangement of highly reactive nitrile imines
derived from
N
-2-nitrophenyl hydrazonyl bromides
can be harnessed for the facile construction of amide bonds. This
amidation reaction was found to be widely applicable to the synthesis
of primary, secondary, and tertiary amides and was used as the key
step in the synthesis of the lipid-lowering agent bezafibrate. The
orthogonality and functional group tolerance of this approach was
exemplified by the
N
-acylation of unprotected amino
acids.
We report the use of N-2,4-dinitrophenyltetrazoles as latent active esters (LAEs) in the synthesis of amide bonds. Activating the tetrazole generates an HOBt-type active ester without the requirement for exogenous coupling agents. The methodology was widely applicable to a range of substrates, with up to quantitative yields obtained. The versatility and functional group tolerance were exemplified with the one-step synthesis of various pharmaceutical agents and the N-acylation of resin-bound peptides.
The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration‐resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand‐binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.
Interaction with cardiac ion channels can potentially result in severe or even fatal cardiac side effects. The most prominent of cardiac channels, human ether-a-go-go-related gene (hERG), voltage-gated sodium channel 1.5 (NaV1.5) and voltage-gated calcium channel 1.2 (CaV1.2), which traffic major ion currents shaping cardiac action potential, are recognized as primary counter-screen targets. These channels possess relatively large inner pores with multiple binding sites and can accommodate a variety of structurally diverse ligands. This chapter provides a short overview of in vitro approaches in preclinical cardiotoxicity screening, gives a summary of available structural data and pharmacophore models for hERG, NaV1.5 and CaV1.2 as well as discusses medicinal chemistry strategies that were successfully applied to mitigate cardiotoxicity risk. The major highlighted approaches are lipophilicity reduction, basicity reduction and removal or modification of (hetero)aromatic substituents. The strategies are illustrated by multiple examples from recent literature.
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