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Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1 H )-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC 50 = 12.7 nM) and CDK9 (IC 50 = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π-π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.

The C-terminal domain of the bacterial transcription antiterminator RfaH undergoes a dramatic all-α-helix to all-β-barrel transition when released from its N-terminal domain. These two distinct folding patterns correspond to different functions: the all-α state acts as an essential regulator of transcription to ensure RNA polymerase binding, whereas the all-β state operates as an activator of translation by interacting with the ribosomal protein S10 and recruits ribosomal mRNA. Accordingly, this drastic conformational change enables RfaH to physically couple the transcription and translation processes in gene expression. To understand the mechanism behind this extraordinary functionally relevant structural transition, we constructed Markov state models using an adaptive seeding method. The constructed models highlight several parallel folding pathways with heterogeneous molecular mechanisms, which reveal the folding kinetics and atomic details of the conformational transition.

A new strategy for diversity-oriented direct glycosylation of bioactive small molecules was developed. This reaction features (−)-β-pinene as acid scavenger and work with glycosyl iodides under mild conditions. With the aid of RP-HPLC and chiral SFC separation techniques, the new direct glycosylation proved effective at gram scale on bioactive small molecules including AZD6244, podophyllotoxin, paclitaxel, and docetaxel. Interesting glycoside derivatives were efficiently created with good yields and 1,2-cis selectivity.

This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n . Compound 9n exhibits effective in vitro activity against A431(WT,overexpression) and H1975([L858R/T790M]) cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.

Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.

An efficient tandem route to the synthesis of 3H-1,2a(1),3-triazaacenaphthylene derivatives of the cyclazine family has been developed. Target compounds were obtained in moderate to good yields by a Yb(OTf)(3)/Ag(2)CO(3)-catalyzed, three-component domino reaction. This in turn will set the stage for a wide application of this useful reaction for the synthesis of structurally diverse polyheterocyclic skeletons containing the imidazo[1,2-a]pyridine privileged structure.

On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.

Fast and accurate predicting of the binding affinities of large sets of diverse protein−ligand complexes is an important, yet extremely challenging, task in drug discovery. The development of knowledge-based scoring functions exploiting structural information of known protein−ligand complexes represents a valuable contribution to such a computational prediction. In this study, we report a scoring function named IPMF that integrates additional experimental binding affinity information into the extracted potentials, on the assumption that a scoring function with the "enriched" knowledge base may achieve increased accuracy in binding affinity prediction. In our approach, the functions and atom types of PMF04 were inherited to implicitly capture binding effects that are hard to model explicitly, and a novel iteration device was designed to gradually tailor the initial potentials. We evaluated the performance of the resultant IPMF with a diverse set of 219 protein-ligand complexes and compared it with seven scoring functions commonly used in computer-aided drug design, including GLIDE, AutoDock4, VINA, PLP, LUDI, PMF, and PMF04. While the IPMF is only moderately successful in ranking native or near native conformations, it yields the lowest mean error of 1.41 log K(i)/K(d) units from measured inhibition affinities and the highest Pearson's correlation coefficient of R(p)2 0.40 for the test set. These results corroborate our initial supposition about the role of "enriched" knowledge base. With the rapid growing volume of high-quality structural and interaction data in the public domain, this work marks a positive step toward improving the accuracy of knowledge-based scoring functions in binding affinity prediction.

Protein kinases are attractive targets for therapeutic interventions in many diseases. Due to their importance in drug discovery, a kinase family-specific potential of mean force (PMF) scoring function, kinase-PMF, was developed to assess the binding of ATP-competitive kinase inhibitors. It is hypothesized that target-specific PMF scoring functions may achieve increased performance in scoring along with the growth of the PDB database. The kinase-PMF inherits the functions and atom types in PMF04 and uses a kinase data set of 872 complexes to derive the potentials. The performance of kinase-PMF was evaluated with an external test set containing 128 kinase crystal structures. We compared it with eight scoring functions commonly used in computer-aided drug design, either in terms of the retrieval rate of retrieving "right" conformations or a virtual screening study. The evaluation results clearly demonstrate that a target-specific scoring function is a promising way to improve prediction power in structure-based drug design compared with other general scoring functions. To provide this rescoring service for researchers, a publicly accessible Web site was established at http://202.127.30.184:8080/scoring/index.jsp .

An efficient method for the soluble polymer-supported synthesis of 5-arylidene thiazolidinones and pyrimidinones using aniline as a traceless linker was described. Aldehyde substrates were attached to the polyethylene glycol (PEG)-bound aniline via an imine linkage, and after the subsequent PEG-promoted Suzuki coupling reaction for the diversification, Knoevenagel condensation was readily employed as the cleavage strategy.

The Lamarckian genetic algorithm of AutoDock 3.0 has been employed to dock 40 1,5-diarylpyrazole class compounds into the active sites of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters and RMSD values compared with the known inhibitor, SC-558 (43), show that these inhibitors interact respectively with COX-2 and COX-1 in a very similar way. The r(2) values of 0.648 for COX-2 and 0.752 for COX-1 indicate that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of 1,5-diarylpyrazoles were reasonably explored, and the COX-2/COX-1 selectivity was demonstrated by the three-dimensional (3D) interaction models of inhibitors complexing with these two enzymes. Using the binding conformations of 1,5-diarylpyrazoles, consistent and highly predictive 3D quantitative structure-activity relationship (QSAR) models were developed by performing comparative molecular field analyses (CoMFA) and comparative molecular similarity analyses (CoMSIA). The q(2) values are 0.635 and 0.641 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by SC-558 (43) and a set of 10 other compounds that were not included in the training set. Mapping these models back to the topology of the active site of COX-2 leads to a better understanding of vital diarylpyrazole compounds and COX-2 interactions. Structure-based investigations and the final 3D QSAR results provided possible guidelines and accurate activity predictions for novel inhibitor design.