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The applications of geostationary (GEO) satellite measurements at an unprecedented spatial and temporal resolution from the Geostationary Environment Monitoring Spectrometer (GEMS) for monitoring and forecasting the alarming ozone pollution in Asia through data assimilation remain at the early stage. Here we investigate the benefit of multiple ozone observations from GEMS geostationary satellite, low Earth orbit (LEO) satellite, and surface networks on summertime ozone simulations through individual or joint data assimilation, built on our previous observing system simulation experiment (OSSE) framework (Shu et al., 2022). We find that data assimilation improves the monitoring of exceedance, spatial patterns, and diurnal variations of surface ozone, with a regional mean negative bias reduction from 2.1 to 0.2–1.2 ppbv in ozone simulations as well as significant improvements of a root-mean-square error (RMSE) of by 5 %–69 % in most Asian countries. Furthermore, the joint assimilation of GEMS and surface observations performs the best. GEMS also brings direct added value for better reproducing ozone vertical distributions, especially in the middle to upper troposphere at low latitudes, but may mask the added value of LEO measurements, which are crucial to constrain surface and upper tropospheric ozone simulations when observations from other platforms are inadequate. Our study provides a valuable reference for ozone data assimilation as multisource observations become gradually available in the era of GEO satellites.

Androgen receptor (AR) has proved to be a vital drug target for treating prostate cancer. Here, we reported the discovery of a novel AR antagonist 92 targeting the AR ligand-binding pocket, but distinct from the marketed drug enzalutamide (Enz), 92 demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization, which is a novel mechanism reported for the first time. First, a novel hit (26, IC50 = 5.57 μM) was identified through virtual screening based on a theoretical AR LBD dimer bound with the Enz model. Then, guided by molecular modeling, 92 was discovered with 32.7-fold improved AR antagonistic activity (IC50 = 0.17 μM). Besides showing high bioactivity and safety, 92 can inhibit AR nuclear translocation. Furthermore, 92 inhibited the formation of the AR LBD dimer, possibly through attenuating the hydrogen-bonding network between the two monomers. This interesting finding would pave the way for the discovery of a new class of AR antagonists.

Mitogen-activated protein kinase FgGpmk1 plays vital roles in the development and virulence of Fusarium graminearum (F. graminearum), the causative agent of Fusarium head blight (FHB). However, to date, the druggability of FgGpmk1 still needs verification, and small molecules targeting FgGpmk1 have never been reported. Here, we reported the discovery of a novel inhibitor 94 targeting FgGpmk1. First, a novel hit (compound 21) with an EC50 value of 13.01 μg·mL-1 against conidial germination of F. graminearum was identified through virtual screening. Then, guided by molecular modeling, compound 94 with an EC50 value of 3.46 μg·mL-1 was discovered, and it can inhibit the phosphorylation level of FgGpmk1 and influence the nuclear localization of its downstream FgSte12. Moreover, 94 can inhibit deoxynivalenol biosynthesis without any damage to the host. This study reported a group of FgGpmk1 inhibitors with a novel scaffold, which paves the way for the development of potent fungicides to FHB management.

The molecular mechanics/generalized Born surface area (MM/GBSA) has been widely used in end-point binding free energy prediction in structure-based drug design (SBDD). However, in practice, it is usually being treated as a disputed method mostly because of its system dependence. Here, combining with machine-learning optimization, we developed a novel version of MM/GBSA, named variable atomic dielectric MM/GBSA (VAD-MM/GBSA), by assigning variable dielectric constants directly to the protein/ligand atoms. The new strategy exhibits markedly improved accuracy in binding affinity calculations for various protein-ligand systems and is promising to be used in the postprocessing of structure-based virtual screening. Moreover, VAD-MM/GBSA outperformed prime MM/GBSA in Schrödinger software and showed remarkable predictive performance for specific protein targets, such as POL polyprotein, human immunodeficiency virus type 1 (HIV-1) protease, etc. Our study showed that the VAD-MM/GBSA method with little extra computational overhead provides a potential replacement of the MM/GBSA in AMBER software. An online web server of VAD-MMGBSA has been developed and is now available at http://cadd.zju.edu.cn/vdgb.

The androgen receptor is a ligand-dependent transcriptional factor and an essential therapeutic target for prostate cancer. Competitive binding of antagonists to the androgen receptor can alleviate aberrant activation of the androgen receptor in prostate cancer. In recent years, computer-aided drug design has played an essential part in the discovery of novel androgen receptor antagonists. This review summarizes the recent advances in the discovery of novel androgen receptor antagonists through computer-aided drug design approaches; and discusses the applications of molecular modeling techniques to understand the resistance mechanisms of androgen receptor antagonists at the molecular level.

Background: The cyanoacrylate fungicide phenamacril targeting fungal myosin I has been widely used for controlling Fusarium head blight (FHB) of wheat caused by the pathogenic fungus Fusarium graminearum worldwide. Therefore, there is great interest in the discovery and development of novel FgMyo1 inhibitors through structure-based drug design for the treatment of FHB. Results: In this study, the binding mechanism of phenamacril with the FgMyo1 was predicted by an integrated molecular modeling strategy. The predicted key phenamacril-binding residues of FgMyo1 were further experimentally validated by point mutagenesis and phenamacril sensitivity assessment. Four novel key residues responsible for phenamacril binding were identified, highlighting the reliability of the theoretical predictions. The subsequent optimization of phenamacril derivatives led to the discovery of a novel compound 10, which shows better activity than phenamacril against conidial germination of F. graminearum, but not against other fungal species. Moreover, 10 also inhibits conidial germination of phenamacril-resistant strains effectively. Further experiments illustrated that application of compound 10 could dramatically inhibit deoxynivalenol (DON) biosynthesis. Conclusion: Overall, our results further optimize and develop the binding model of phenamacril-myosin I. Furthermore, compound 10 was found and has the potential to be developed as a species-specific fungicide for management of FHB. This article is protected by copyright. All rights reserved.

When nonsurgical endodontic treatment fails, surgical treatment is an alternative approach for treating periapical disease. However, endodontic microsurgery (EMS), particularly in anatomically challenging areas, such as the posterior teeth, is a skill-sensitive task that can present a unique set of challenges for the surgeon. In recent years, digital guidance technology has been applied more frequently in dentistry. Dynamic navigation (DN) is a pioneering technology that uses an optical positioning device controlled by a sophisticated computerized interface and dedicated three-dimensional surgical path planning software program. This technique has also recently been introduced in the field of EMS to improve accuracy and avoid related complications. This case report presents a novel approach to DN-assisted EMS and describes its application in posterior teeth. After undergoing DN-assisted EMS, all patients were completely asymptomatic at the follow-up visit. Radiographic examinations performed immediately and 3-9 months after EMS revealed that the root resection was performed accurately without complications. The DN technique has been proven to be a feasible, predictable, and time-saving system for assisting EMS in cases requiring treatment in anatomically challenging areas, such as in the posterior teeth.

Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function‐2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure‐based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP‐19 exhibits the best anti‐inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor‐kappa B signaling pathway, which is comparable to that of DEX. HP‐19 also does not induce adverse effect‐related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators., The glucocorticoid receptor (GR) ligand binding domain structural ensemble is characterized by the molecular dynamics (MD) simulations and Markov state model analysis. Based on the GR antagonist conformations sampled by MD simulations, virtual screening and in vitro bioassays are performed. Six novel GR ligands with anti‐inflammatory activities are discovered. HP‐19 is a promising candidate for the development of GR modulators.

Mitogen-activated protein kinase FgGpmk1 plays vital roles in the development and virulence of

Lung cancer is a leading cause of cancer-related death worldwide. Cyanopyridines and aminocyanopyridines with carbon-nitrogen bonds have been proved to exert significant anticancer, antibacterial, and anti-inflammatory effects. In this study, we showed that aminocyanopyridine 3o and 3k displaying potent antitumor activity via inhibiting the signal transducer and activator of transcription 3 (STAT3) pathway. They blocked the constitutive STAT3 phosphorylation in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptosis factors. Most importantly, 3o also inhibited interleukin-6-induced STAT3 activation and nuclear localization. Furthermore, 3o significantly inhibited the tumor growth of H460-derived xenografts. Taken together, these findings suggest that 3o and 3k are promising therapeutic drug candidates for lung cancer by inhibiting persistent STAT3 signaling.

DNA methyltransferases (DNMTs), responsible for the regulation of DNA methylation, have been regarded as promising drug targets for cancer therapy. However, high structural conservation of the catalytic domains of DNMTs poses a big challenge to design selective inhibitors for a specific DNMT isoform. In this study, molecular dynamics (MD) simulations, end-point free energy calculations and umbrella sampling (US) simulations were performed to reveal the molecular basis of the binding selectivity of three representative DNMT inhibitors towards DNMT1 and DNMT3A, including SFG (DNMT1 and DNMT3A dual inhibitors), DC-05 (DNMT1 selective inhibitor) and GSKex1 (DNMT3A selective inhibitor). The binding selectivity of the studied inhibitors reported in previous experiments is reproduced by the MD simulation and binding free energy prediction. The simulation results also suggest that the driving force to determine the binding selectivity of the studied inhibitors stems from the difference in the protein-inhibitor van der Waals interactions. Meanwhile, the per-residue free energy decomposition reveals that the contributions from several non-conserved residues in the binding pocket of DNMT1/DNMT3A, especially Val1580/Trp893, Asn1578/Arg891 and Met1169/Val665, are the key factors responsible for the binding selectivity of DNMT inhibitors. In addition, the binding preference of the studied inhibitors was further validated by the potentials of mean force predicted by the US simulations. This study will provide valuable information for the rational design of novel selective inhibitors targeting DNMT1 and DNMT3A.

The number of solved G-protein-coupled receptor (GPCR) crystal structures has expanded rapidly, but most GPCR structures remain unsolved. Therefore, computational techniques, such as homology modeling, have been widely used to produce the theoretical structures of various GPCRs for structure-based drug design (SBDD). Due to the low sequence similarity shared by the transmembrane domains of GPCRs, accurate prediction of GPCR structures by homology modeling is quite challenging. In this study, angiotensin II type I receptor (AT1R) was taken as a typical case to assess the reliability of class A GPCR homology models for SBDD. Four homology models of angiotensin II type I receptor (AT1R) at the inactive state were built based on the crystal structures of CXCR4 chemokine receptor, CCR5 chemokine receptor, and δ-opioid receptor, and refined through molecular dynamics (MD) simulations and induced-fit docking, to allow for backbone and side-chain flexibility. Then, the quality of the homology models was assessed relative to the crystal structures in terms of two criteria commonly used in SBDD: prediction accuracy of ligand-binding poses and screening power of docking-based virtual screening. It was found that the crystal structures outperformed the homology models prior to any refinement in both assessments. MD simulations could generally improve the docking results for both the crystal structures and homology models. Moreover, the optimized homology model refined by MD simulations and induced-fit docking even shows a similar performance of the docking assessment to the crystal structures. Our results indicate that it is possible to establish a reliable class A GPCR homology model for SBDD through the refinement by integrating multiple molecular modeling techniques.

Survivin is the smallest member of IAP (inhibitor of apoptosis protein) family, which plays important roles in both mitosis and apoptosis. It has become an attractive drug target due to its overexpression in many human cancers. Survivin has been proven to bind to Smac/DIABLO protein that indirectly inhibits apoptosis. Meanwhile, it is the key subunit of chromosome passenger complex (CPC) which bind to the N-terminal tail of phosphorylated histone H3T3ph during mitosis. Up to now, Survivin directly targeting inhibitor has yet to merge since the difficulty of disrupting the protein-protein interactions (PPIs) between Survivin and its substrate proteins. Nevertheless, currently known binding partners of Survivin provide crucial information about conserved recognition mechanism, which can assist in the detection of some uncharted substrates and also the Survivin inhibitors. Herein, we adopted a method that using four substrates to analyze the common binding mode of Survivin. To accomplish this, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized born surface area (MM-GBSA) binding free energy calculations and energy decomposition were carried out to assess the binding affinity and per-residue contributions. We found that there are two anchor sites of Survivin responsible for maintaining the binding conformation and one sub-pocket for intermolecular recognition. The results of this study synthetically describe the binding mechanism and provide valuable guidance for rational drug design of PPI inhibitor.

The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF-3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa.

Molecular hybridization is considered as an effective tactic to develop drugs for the treatment of cancer. A series of novel hybrid compounds of isatin and Michael acceptor were designed and synthesized on the basis of association principle. These hybrid compounds were tested for cytotoxic potential against human cancer cell lines namely, BGC-823, SGC-7901 and NCI-H460 by MTT assay. Most compounds showed good anti-growth activities in all tested human cancer cells. SAR and QSAR analysis may provide vital information for the future development of novel anti-cancer inhibitors. Notably, compound 6a showed potent growth inhibition on BGC-823, SGC-7901 and NCI-H460 with the IC50 values of 3.6 ± 0.6, 5.7 ± 1.2, 3.2 ± 0.7 μM, respectively. Besides, colony formation assays, wound healing assays and flow cytometry analysis indicated 6a exhibited a potent anti-growth and anti-migration ability in a concentration-dependence manner through arrested cells in the G2/M phase of cell cycle. Moreover, 6a significantly repressed tumor growth in a NCI-H460 xenograft mouse model. Overall, our findings suggested isatin analogues inspired Michael acceptor may provide promising lead compounds for the development of cancer chemotherapeutics.

Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field.

Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFRT790M secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three-step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFRT790M-driven NSCLC.

Fibroblast growth factor receptor 1 (FGFR1), belonging to receptor tyrosine kinases (RTKs), possesses various biological functions. Over-expression of FGFR1 has been observed in multiple human malignancies. Hence, targeting FGFR1 is an attractive prospect for the advancement of cancer treatment options. Here, we present a novel small molecular FGFR1 inhibitor L16H50, which can inhibit FGFR1 kinase in an ATP-independent manner. It potently inhibits FGFR1-mediated signaling in a gastric cancer cell line, resulting in inhibition of cell growth, survival and migration. It also displays an outstanding anti-tumor activity in a gastric cancer xenograft tumor model by targeting FGFR1 signaling. These results show that L16H50 is a potent non-ATP-competitive FGFR1 inhibitor and may provide strong rationale for its evaluation in gastric cancer patients.

Obesity increases the risk for a number of diseases including cardiovascular diseases and type 2 diabetes. Excess saturated fatty acids (SFAs) in obesity play a significant role in cardiovascular diseases by activating innate immunity responses. However, the mechanisms by which SFAs activate the innate immune system are not fully known. Here we report that palmitic acid (PA), the most abundant circulating SFA, induces myocardial inflammatory injury through the Toll-like receptor 4 (TLR4) accessory protein MD2 in mouse and cell culture experimental models. Md2 knockout mice are protected against PA- and high-fat diet-induced myocardial injury. Studies of cell surface binding, cell-free protein–protein interactions and molecular docking simulations indicate that PA directly binds to MD2, supporting a mechanism by which PA activates TLR4 and downstream inflammatory responses. We conclude that PA is a crucial contributor to obesity-associated myocardial injury, which is likely regulated via its direct binding to MD2.

Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. Resveratrol and curcumin are proven to have potent anti-inflammatory efficacy, but their clinical application is limited by their metabolic instability. Here, a series of resveratrol and the Mono-carbonyl analogs of curcumin (MCAs) hybrids were designed and synthesized by efficient aldol construction strategy, and then screened for anti-inflammatory activities in vitro and in vivo. The results showed that the majority of analogs effectively inhibited the LPS-induced production of IL-6 and TNF-α. Five analogs, a9, a18, a19, a20 and a24 exhibited excellent anti-inflammatory activity in a dose-dependent manner along with low toxicity in vitro. Structure activity relationship study revealed that the electron-withdrawing groups at meta-position and methoxyl group (OCH3) at the para position of the phenyl ring were important for anti-inflammatory activities. The most promising compound a18 decreased LPS induced TNF-α, IL-6, IL-12, and IL-33 mRNA expression. Additionally, a18 significantly protected against LPS-induced acute lung injury in the in vivo mouse model. The research of resveratrol and MCAs hybrids could bring insight into the treatment of inflammatory diseases and compound a18 may serve as a lead compound for the development of anti-ALI agents.

Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 μM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.

Significance Genetic copy number variations (CNVs) are the most common mechanism of structural genetic diversity, playing a key role in human health and common diseases. However, because of a lack of relevant experimental models, little is known about how rare CNVs contribute to the risk of complex phenotypes. We show that transgenic mice with high copy number of DEFA1/DEFA3 [encoding human neutrophil peptides 1–3 (HNP1–3)] suffer from more severe sepsis because of more extensive endothelial barrier dysfunction and endothelial cell pyroptosis. Functional blockade of HNP1–3 rescues the mice from lethal sepsis. These findings exemplify how CNVs modulate disease development in appropriate animal models and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information., Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1–3 (HNP1–3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.

A series of tetrahydrobenzothieno[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, (1) H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure-activity relationship analyses indicated that compounds with an aromatic ring substituted in the C-2 position or with larger molecules such as 3g, 4c, and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μm), was identified to have the most potent antitumor activities, with IC50 values of 7.7, 18.9, and 13.3 μm against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3-d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1-mediated cancers.

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC50 = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases. Keywords: Androgen receptor, AR ligand, Virtual screening, AR agonist, AR antagonist

Myeloid differentiation protein 2 (MD2), together with Toll-like receptor 4 (TLR4), binds lipopolysaccharide (LPS) with high affinity, inducing the formation of the activated homodimer LPS-MD2-TLR4. MD2 directly recognizes the Lipid A domain of LPS, leading to the activation of downstream signaling of cytokine and chemokine production, and initiation of inflammatory and immune responses. However, excessive activation and potent host responses generate severe inflammatory syndromes such as acute sepsis and septic shock. MD2 is increasingly being considered as an attractive pharmacological target for the development of potent anti-inflammatory agents. In this Keynote review, we provide a comprehensive overview of the recent advances in the structure and biology of MD2, and present MD2 modulators as promising agents for anti-inflammatory intervention.

EF24 is an IKKβ inhibitor (IC50: 72 μM) containing various anti-tumor activities. In this study, a series of EF24 analogs targeting IKKβ were designed and synthesized. Several IKKβ inhibitors with better activities than EF24 were screened out and B3 showed best IKKβ inhibitory (IC50: 6.6 μM). Molecular docking and dynamic simulation experiments further confirmed this inhibitory effect. B3 obviously suppressed the viability of Hela229, A549, SGC-7901 and MGC-803 cells. Then, in SGC-7901 and MGC-803 cells, B3 blocked the NF-κB signal pathway by inhibiting IKKβ phosphorylation, and followed arrested the cell cycle at G2/M phase by suppressing the Cyclin B1 and Cdc2 p34 expression, induced the cell apoptosis by down-regulating Bcl-2 protein and up-regulating cleaved-caspase3. Moreover, B3 significantly reduced tumor growth and suppressed the IKKβ-NF-κB signal pathway in SGC-7901 xenograft model. In total, this study present a potential IKKβ inhibitor as anti-tumor precursor.

Acute lung injury (ALI) has a high lethality rate, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute most to tissue deterioration in cases of ALI. In this study, we designed and synthesized a new series of thiazolo[3,2-a]pyrimidine derivatives based on a previously identified lead compound, and we evaluated their anti-inflammatory activities. Structure-activity relationship studies led to the discovery of two highly potent inhibitors. The two promising compounds were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner in mouse primary peritoneal macrophages (MPMs). Furthermore, administration of these compounds resulted in lung histopathological improvements and attenuated LPS-induced ALI in vivo. Taken together, these data indicate that these novel thiazolo[3,2-a]pyrimidine derivatives could be developed as candidate drugs for the treatment of ALI.

The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4. In this study, conventional molecular dynamics (MD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations and umbrella sampling (US) simulations were carried out to reveal the principle of the binding preference of ponatinib and AZD4547 towards FGFR4/FGFR1. The results provided by MM/GBSA illustrate that ponatinib has similar binding affinities to FGFR4 and FGFR1, while AZD4547 has much stronger binding affinity to FGFR1 than to FGFR4. A comparison of the individual energy terms suggests that the selectivity of AZD4547 towards FGFR1 versus FGFR4 is primarily controlled by the variation of the van der Waals interactions. The US simulations reveal that the PMF profile of FGFR1/AZD4547 has more peaks and valleys compared with that of FGFR4/AZD4547, suggesting that the dissociation process of AZD4547 from FGFR1 are easily trapped into local minima. Moreover, it is observed that FGFR1/AZD4547 has much higher PMF depth than FGFR4/AZD4547, implying that it is more difficult for AZD4547 to escape from FGFR1 than from FGFR4. The physical principles provided by this study extend our understanding of the binding mechanisms and provide valuable guidance for the rational design of FGFR isoform selective inhibitors.

Accumulating evidence suggests that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. Based on our previous discovery of two non-ATP competitive FGFR1 inhibitors, A114 and A117, we designed and screened a series of compounds with the framework of bisaryl-1,4-dien-3-one. Among them, D12 and D15 exhibited the most potent FGFR1 inhibitory activity, which was ATP-independent. Furthermore, a quantitative structure-activity relationship analysis of 41 analogs demonstrated that the specific structural substitutions alter their bioactivities. Molecular docking and dynamics simulation analysis indicated the hydrophobic interaction at the FGFR1-D12/D15 interaction was dominant. Evaluation for anti-gastric cancer efficacy of D12 and D15 indicated effective inhibition of cell proliferation, apoptosis induction and cell cycle arrest. Thus, these two FGFR1 inhibitors have therapeutic potential in the treatment of gastric cancer, and this study provides will contribute to the rational design of novel non-ATP competitive FGFR1 inhibitors.

Nineteen metabolites with diverse structures, including the rare pyrroloindoline alkaloid verrupyrroloindoline (1), the unprecedented highly fused benzosesquiterpenoid verrubenzospirolactone (2), the new asteriscane-type sesquiterpenoid 10-deoxocapillosanane D (3), and the two new cyclopentenone derivatives (4S*,5S*)-4-hydroxy-5-(hydroxymethyl)-2,3-dimethyl-4-pentylcyclopent-2-en-1-one (4) and (S)-4-hydroxy-5-methylene-2,3-dimethyl-4-pentylcyclopent-2-en-1-one (5), were isolated from a South China Sea collection of the soft coral Sinularia verruca. Eleven previously described marine metabolites (7–15, 18, and 19) were also obtained as well as three new EtOH-adduct artifacts (6, 16, and 17). The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with previously reported data. Compounds 4, 5, and 16 showed protection against the cytopathic effects of HIV-1 infection with EC50 values of 5.8–34 μM, and 4, 6, and 16 exhibited inhibition against LPS-induced NO production with IC50 values of 24–28 μM.

Curcumin, a natural product, has been shown to possess notable anti-inflammatory activities and numerous studies have been carried out on its clinical applications. Recently, several reports mentioned that myeloid differentiation protein 2 (MD-2) may be the direct target of curcumin in the inhibition of lipopolysaccharide (LPS) signaling. However, the exact interaction between curcumin and MD-2 is still incompletely understood. In the present study, computational and experimental methods were employed to explore the underlying structural mechanism of curcumin binding to the MD-2 protein. Molecular docking and molecular dynamics (MD) simulation studies showed that curcumin could be embedded into the hydrophobic pocket of MD-2 and form stable hydrogen bonding interactions with residues R90 and Y102 of MD-2. Moreover, experimental results of curcumin binding to the MD-2(R90A/Y102A) mutant further confirmed that residues ARG-90 and TYR-102 contribute to the recognition process of curcumin binding to the MD-2 protein. In conclusion, we have explored the binding mechanism of curcumin to MD-2; more importantly, this work could offer useful references for designing novel analogs of curcumin as potential anti-inflammatory agents targeting the MD-2 protein.