The androgen receptor (AR) regulates gene transcription in many tissues and is profoundly important in prostate cancer. Antiandrogens compete with the natural hormone and are front line therapeutics to treat prostate cancer. However, antiandrogens frequently become ineffective after prolonged treatment because of development of tumor resistance. This paper reviews design principles for new generations of antiandrogens: super antagonists and surface allosteric modulators. Super antiandrogens are compounds with higher binding affinity than natural agonists and that contain precisely engineered hydrophobic groups that disrupt AR function. AR surface is also an attractive alternative target. Surface inhibitors are small molecules that directly block the receptor-co-activator interface, preventing co-activator recruitment. The challenges to designing these compounds are significant but so is the potential for treatment of the disease.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
"Consequently antagonist-like H12 conformation/s are thought to prevent the correct surface arrangement of AF-2 for productive co-activator binding (78). The AR LBD has also been shown to feature another hydrophobic exposed groove susceptible of pharmaceutical attack called Binding Function 3 (BF-3), which has been shown to modulate coactivator recruitment via allosteric communication and it is hypothesized to be implicated in the recruitment of AR coregulatory proteins and is also an emerging non-LBP druggable site         . This surface is adjacent to AF-2 coactivator binding pocket and comprises residues (I672, F673, P723, G724, N727, F826, Q829, Q837, N833 and R84), belonging to H1, H3-5 and H9 . "
[Show abstract][Hide abstract] ABSTRACT: The androgen receptor (AR) has been extensively studied for more than eight decades, due to its regulatory role in the development and maintenance of sexual phenotypes. AR deregulation and association to pathogenesis quickly defined AR as a major target in hormonally responsive diseases such as all stages of prostate cancer (PCa) or androgen insensitivity syndromes (AIS). However, even though there are currently five FDA approved drugs for PCa, AR has been, and still is, a very challenging target due to the disease progression to castrationresistant stages. Several AR-related alterations have been rationalized thanks to structural and functional studies. Due to the hypothesized highly dynamic and flexible nature of AR multi domain structure, many of its physiologically relevant structural states still lack experimental detailed confirmation. However, elucidation of the crystal structures of AR ligand-binding domain (LBD) cocooning the natural ligand dihydrotestosterone as well as the synthetic metribolone bound to its ligand binding pocket (LBP) opened a new window into modulating the mechanism of action of this protein in disease. AR encapsulation of bound ligands reshapes its protein-protein interacting surfaces influencing key macromolecular assemblies. Also may hold true the hypothesis that structural coupling of surface conformations, due to the concrete cellular milieu of coregulators present, may determine differential tissue-specific ligand activities. Additionally, non-ligand binding pocket (non-LBP) druggable sites on the AR LBD and NTD are emerging as alternatives that open rational drug avenues to explore novel anti-androgenic scaffolds. However, a deeper understanding into AR structural plasticity and function in disease still poses many challenges ahead.
[Show abstract][Hide abstract] ABSTRACT: When hormone binds to the androgen receptor (AR), the ligand-binding domain (LBD) becomes ordered, displaying a new protein–protein
interaction surface called AF2 (coactivator-binding pocket), which is a hydrophobic groove that fits AR coregulators. The
association of coregulators with AR LBD is often a critical step for its transcriptional function. Existing pharmaceuticals
block AR activity by disrupting AF2 surface's ability to recruit coactivators. Such antagonists bind to the hormone-binding
site inside the LBD core and perturb the structure of the most terminal helix of the LBD, distorting the AF2 surface. The
AF2 pocket is also a potential candidate for pharmaceutical intervention by surface-directed small molecules that will directly
block coactivator recruitment. Such molecules may be a novel generation of antiandrogens for treating prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using molecular dynamics with a binary solvent. Furthermore, analysis of the simulations give direct access to interaction free energies between the protein and small organic molecules, which can be used to detect binding sites and to predict the maximal affinity that a drug-like molecule could attain for them. On a set of pharmacologically relevant proteins, we obtain good predictions for druggable sites as well as for protein-protein and low affinity binding sites. This is the first druggability index not based on surface descriptors and, being independent of a training set, is particularly indicated to study unconventional targets such as protein-protein interactions or allosteric binding sites.
No preview · Article · Apr 2009 · Journal of Medicinal Chemistry