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Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62 , which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development. Based on the rediscovery of a reported RIPK3 inhibitor (GSK'840) and structure-guided lead optimization, a potent, selective, and orally bioavailable type-II kinase inhibitor of RIPK1 (62) has been developed. [Display omitted] [ABSTRACT FROM AUTHOR]

The human formyl peptide receptor 2 (FPR2) plays a crucial role in host defense and inflammation, and has been considered as a drug target for chronic inflammatory diseases. A variety of peptides with different structures and origins have been characterized as FPR2 ligands. However, the ligand-binding modes of FPR2 remain elusive, thereby limiting the development of potential drugs. Here we report the crystal structure of FPR2 bound to the potent peptide agonist WKYMVm at 2.8 Å resolution. The structure adopts an active conformation and exhibits a deep ligand-binding pocket. Combined with mutagenesis, ligand binding and signaling studies, key interactions between the agonist and FPR2 that govern ligand recognition and receptor activation are identified. Furthermore, molecular docking and functional assays reveal key factors that may define binding affinity and agonist potency of formyl peptides. These findings deepen our understanding about ligand recognition and selectivity mechanisms of the formyl peptide receptor family. Formyl peptide receptors (FPRs) are GPCRs that play important roles in transducing chemotactic signals in phagocytes and mediating host-defense and inflammatory responses. Here the authors present the 2.8 Å crystal structure of human FPR2 in complex with the peptide agonist WKYMVm and in combination with molecular docking, ligand-binding and signalling assays provide further insights into the binding modes of FPR2 to both non-formyl and formyl peptides. [ABSTRACT FROM AUTHOR]

[Display omitted] • A fragment-based hit screening resulted in several fragment inhibitors of the ZIKV NS2B/NS3 protease. • Crystal structures of the ZIKV NS2B/NS3 protease in complex with a tetrapeptide and a fragment were determined, revealing the detailed but distinct protease-inhibitor interaction patterns. • A novel inhibitor with a higher ligand-binding efficiency was designed based on two complex structures. Zika virus (ZIKV) has been a serious public health problem, and there is no vaccine or drug approved for the prevention or treatment of ZIKV yet. The ZIKV NS2B/NS3 protease plays an important role in processing the virus precursor polyprotein and is thus a promising target for antiviral drugs development. In order to discover novel inhibitors of this protease, we carried out a fragment-based hit screening and characterized protein-inhibitor interactions using the X-ray crystallography together with isothermal titration calorimetry. We reported two high-resolution crystal structures of the protease (bZiProC143S) in complex with an active fragment as well as a tetrapeptide, revealing that there is domain swapping in the protein structures and two ligands only occupy the substrate-binding pocket of one copy in a symmetric unit. Based on the detailed binding modes of two ligands revealed by crystal structures, we designed a novel inhibitor which inhibits the NS2B/NS3 protease with a higher potency than the fragment and possesses a higher ligand-binding efficiency and a comparable IC 50 compared to the tetrapeptide. These results thus provide a structural basis and valuable hint for development of more potent inhibitors of the ZIKV NS2B/NS3 protease. [ABSTRACT FROM AUTHOR]

The signal transduction of acetylatedhistone can be processedthrough a recognition module, bromodomain. Several inhibitors targetingBRD4, one of the bromodomain members, are in clinical trials as anticancerdrugs. Hereby, we report our efforts on discovery and optimizationof a new series of 2-thiazolidinones as BRD4 inhibitors along ourprevious study. In this work, guided by crystal structure analysis,we reversed the sulfonamide group and identified a new binding mode.A structure–activity relationship study on this new seriesled to several potent BRD4 inhibitors with IC50of about0.05–0.1 μM in FP binding assay and GI50of0.1–0.3 μM in cell based assays. To complete the lead-likeassessment of this series, we further checked its effects on BRD4downstream protein c-Myc, investigated its selectivity among fivedifferent bromodomain proteins, as well as the metabolic stabilitytest, and reinforced the utility of 2-thiazolidinone scaffold as BETbromodomain inhibitors in novel anticancer drug development. [ABSTRACT FROM AUTHOR]

HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N -(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide ( 108 ) showed high affinity for binding to HSP90 (FP binding assay, IC 50 = 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI 50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. [ABSTRACT FROM AUTHOR]

Abstract: Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20–40nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs. [Copyright &y& Elsevier]

Thesignificance of halogen bonding in protein–ligand interactionshas been recognized recently. We present here the first comprehensivethermodynamic and structural characterization of halogen bonding inPDE5–inhibitor interactions. ITC studies reveal that bindingstrength of the halogen bonding between chlorine, bromine, and iodineof inhibitor and the protein is −1.57, −3.09, and −5.59kJ/mol, respectively. The halogens interact with the designed residueY612 and an unexpected buried water molecule. [ABSTRACT FROM AUTHOR]