Guided
by molecular docking, a commonly used open-chain linker
was cyclized into a five-membered pyrrolidine to lock the overall
conformation of the propeller-shaped molecule. Different substituents
were introduced into the pyrrolidine moiety to block oxidative metabolism.
Surprisingly, it was found that a small methyl substituent could be
used to alleviate the oxidative metabolism of pyrrolidine while maintaining
or enhancing potency, which could be described as a “magic
methyl”. Further optimization around the “3rd blade”
of the propeller led to identification of a series of potent and selective
PI3Kδ inhibitors. Among them, compound 50 afforded
an optimum balance of PK profiles and potency. Oral administration
of 50 attenuated the arthritis severity in a dose-dependent
manner in a collagen-induced arthritis model without obvious toxicity.
Furthermore, 50 demonstrated excellent pharmacokinetic
properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.
Salt-inducible kinases
(SIKs) are calcium/calmodulin-dependent
protein kinase (CAMK)-like (CAMKL) family members implicated in insulin
signal transduction, metabolic regulation, inflammatory response,
and other processes. Here, we focused on SIK2, which is a target of
the Food and Drug Administration (FDA)-approved pan inhibitor
N
-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide
(dasatinib), and constructed four representative SIK2 structures by
homology modeling. We investigated the interactions between dasatinib
and SIK2 via molecular docking, molecular dynamics simulation, and
binding free energy calculation and found that dasatinib showed strong
binding affinity for SIK2. Binding free energy calculations suggested
that the modification of various dasatinib regions may provide useful
information for drug design and to guide the discovery of novel dasatinib-based
SIK2 inhibitors.
The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as the target protein. Molecular dynamics simulations and binding free energy calculations were applied to identify the possible binding sites and understand its recognition ability of the supramolecular inhibitor, the tweezer molecule (CLR01). On the basis of our simulation, major interactions between lysine residues and CLR01 come from the van der Waals interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the inhibitor. Apart from K214, which was found to be crystallized with this inhibitor, other lysine sites have also shown their abilities to form inclusion complexes with the inhibitor. Such non-specific recognition features of CLR01 against 14-3-3σ can be used in the modification of protein functions via supramolecular chemistry.
Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of β-tubulin and its morpholine group lies close to α-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with α-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives, 8a exhibited more than 10-fold antiproliferation activity in several tumor cells than KX01 and significantly improved in vivo antitumor effects. The X-ray crystal structure suggested that 8a both bound to the colchicine site and extended into the interior of α-tubulin to form potent interactions, presenting a novel binding mode. A potential clinical candidate for cancer therapy was identified in this study.
Salt inducible kinase 2 (SIK2) is a calcium/calmodulin-dependent protein kinase-like kinase that is implicated in a variety of biological phenomena, including cellular metabolism, growth, and apoptosis. SIK2 is the key...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.