Highlights d Analysis of TRAP1 dynamics allows discovery of paralogselective allosteric inhibitors d Small molecules targeting TRAP1 revert TRAP1-dependent succinate dehydrogenase inhibition d Allosteric TRAP1 inhibitors abolish tumorigenic growth of neoplastic cells d Selective targeting of TRAP1 activity provides new antagonists of chaperones
Molecular chaperones HSP90 and HSP70 are essential regulators of the folding and activation of a disparate ensemble of client proteins. They function through ATP hydrolysis and the assembly of multiprotein complexes with cochaperones and clients. While their therapeutic relevance is recognized, important details underlying the links between ATP-dependent conformational dynamics and clients/cochaperones recruitment remain elusive. Allosteric modulators represent fundamental tools to obtain molecular insights into functional regulation. By selective perturbation of different aspects of HSP90/HSP70 activities, allosteric drugs can tune rather than completely inhibit signaling cascades, providing information on the relationships between structure-dynamics and function. Herein, we review advances in the design of HSP90 and HSP70 allosteric modulators. We consider inhibitors and activators in different biochemical and disease models. We discuss these compounds as probes to decipher the complexity of the chaperone machinery and that at the same time represent starting leads for the development of drugs against cancer and neurodegeneration.
The diaryl urea is an important fragment/pharmacophore in constructing anticancer molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor. Many novel compounds have been synthesized and evaluated for their antitumor activity with the successful development of sorafenib. Moreover, this structure is used to link alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors: it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh) ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the search to find new and more potent compounds.
Serotonin transporter (SERT) modulates serotonergic signaling via re-uptake of serotonin in pre-synaptic cells. The inclusion in cholesterol-enriched membrane domains is crucial for SERT activity, suggesting a cross-talk between the protein and the sterol. Here, we develop a protocol to identify potential cholesterol interaction sites coupling statistical analysis to multi-microsecond coarse-grained molecular dynamics simulations of SERT in a previously validated raft-like membrane model. Six putative sites were found, including a putative CRAC motif on TM4 and a CARC motif on TM10. Among them, four hot-spots near regions related to ion binding, transport, and inhibition were detected. Our results encourage prospective studies to unravel mechanistic features of the transporter and related drug discovery implications.
The molecular chaperone TRAP1 is the mitochondrial paralog of Hsp90
and is overexpressed in many cancer cells. The orthosteric ATP-binding
site of TRAP1 has been considered the primary inhibitor binding location,
but TRAP1 allosteric modulators have not yet been investigated. Here,
we generated and characterized the Hsp90 inhibitor PU-H71, conjugated
to the mitochondrial delivery vehicle triphenylphosphonium (TPP) with
a C10 carbon spacer, named SMTIN-C10, to enable dual binding
to orthosteric and allosteric sites. In addition to tight binding
with the ATP-binding site through the PU-H71 moiety, SMTIN-C10 interacts
with the E115 residue in the N-terminal domain through the TPP moiety
and subsequently induces structural transition of TRAP1 to a tightly
packed closed form. The data indicate the existence of a druggable
allosteric site neighboring the orthosteric ATP pocket that can be
exploited to develop potent TRAP1 modulators.
We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB To understand the unexpected affinity for the CB receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.
Allosteric
molecules provide a powerful means to modulate protein
function. However, the effect of such ligands on distal orthosteric
sites cannot be easily described by classical docking methods. Here,
we applied machine learning (ML) approaches to expose the links between
local dynamic patterns and different degrees of allosteric inhibition
of the ATPase function in the molecular chaperone TRAP1. We focused
on 11 novel allosteric modulators with similar affinities to the target
but with inhibitory efficacy between the 26.3 and 76%. Using a set
of experimentally related local descriptors, ML enabled us to connect
the molecular dynamics (MD) accessible to ligand-bound (perturbed)
and unbound (unperturbed) systems to the degree of ATPase allosteric
inhibition. The ML analysis of the comparative perturbed ensembles
revealed a redistribution of dynamic states in the inhibitor-bound
versus inhibitor-free systems following allosteric binding. Linear
regression models were built to quantify the percentage of experimental
variance explained by the predicted inhibitor-bound TRAP1 states.
Our strategy provides a comparative MD–ML framework to infer
allosteric ligand functionality. Alleviating the time scale issues
which prevent the routine use of MD, a combination of MD and ML represents
a promising strategy to support
in silico
mechanistic
studies and drug design.
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