Discovery of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors.

Herein, we report the discovery of a series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8k), which showed IC50 values of 0.004 µM and 0.001 µM against ROCK Ⅰ and ROCK Ⅱ, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this study provides a promising lead compound for drug discovery targeting ROCKs.

Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors.

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41±0.03µM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.

Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis.

Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3 µM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22 µM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies.

Discovery of 6-phenylimidazo[2,1-b]thiazole derivatives as a new type of FLT3 inhibitors.

In this investigation, a series of 6-phenylimidazo[2,1-b]thiazole derivatives were synthesized. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell line MV4-11, but very weak or no activity against FLT3-independent human cervical cancer cell line Hela. FLT3 kinase inhibition assays were then performed on the three most active compounds. Among these compounds, 6-(4-(3-(5-(tert-butyl)isoxazol- 3-yl)ureido)phenyl)-N-(3-(dimethylamino)propyl)imidazo[2,1-b]thiazole-3-carboxamide (19) exhibited the highest potency in both cellular (MV4-11, IC50: 0.002 µM) and enzymatic (FLT3, IC50: 0.022 µM) assays. Further in-depth in vitro anti-AML activity and mechanism of action studies were carried out on compound 19.

Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors.

Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 µM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 µM, 13.1 µM and 11.4 µM, respectively.

A preclinical evaluation of a novel multikinase inhibitor, SKLB-329, as a therapeutic agent against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a serious life-threatening malignant disease of liver. Molecular targeted therapies are considered a promising strategy for the treatment of HCC. Sorafenib is the first, and so far the only targeted drug approved by the US Food and Drug Administration (FDA) for clinical therapy of HCC. Despite being effective in some HCC patients, some demerits of sorafenib in the treatment of HCC, such as modest survival benefits, and drug resistance, have also been reported, which highlights the unmet medical need among patients with HCC. Here, we report a novel multikinase inhibitor discovered by us, SKLB-329, which potently inhibits angiogenesis-related kinases including VEGFR1/2/3, and FGFR2, and the Src kinase. SKLB-329 significantly inhibited endothelial cell growth, migration, invasion and tube formation. It showed potent anti-angiogenic activity in a transgenic zebrafish model. Moreover, SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src-mediated FAK and Stat3 activity. In vivo, oral administration of SKLB-329 considerably suppressed the tumor growth in HCC xenograft models (HepG2 and SMMC7721) in a dose-dependent manner. In all of the in vitro and in vivo assays of this investigation, sorafenib was used as a positive control, and in most assays SKLB-329 exhibited a higher potency compared with the positive control. In addition, SKLB-329 also bears favorable pharmacokinetic properties. Collectively, the results of preclinical studies presented here demonstrate that SKLB-329 is a promising drug candidate for HCC treatment.

Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor.

Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an IC(50) value of 7 nM.

[Research progress of the small molecule covalent inhibitors].

Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.

ID-Score: a new empirical scoring function based on a comprehensive set of descriptors related to protein-ligand interactions.

Scoring functions have been widely used to assess protein-ligand binding affinity in structure-based drug discovery. However, currently commonly used scoring functions face some challenges including poor correlation between calculated scores and experimental binding affinities, target-dependent performance, and low sensitivity to analogues. In this account, we propose a new empirical scoring function termed ID-Score. ID-Score was established based on a comprehensive set of descriptors related to protein-ligand interactions; these descriptors cover nine categories: van der Waals interaction, hydrogen-bonding interaction, electrostatic interaction, π-system interaction, metal-ligand bonding interaction, desolvation effect, entropic loss effect, shape matching, and surface property matching. A total of 2278 complexes were used as the training set, and a modified support vector regression (SVR) algorithm was used to fit the experimental binding affinities. Evaluation results showed that ID-Score outperformed other selected commonly used scoring functions on a benchmark test set and showed considerable performance on a large independent test set. ID-Score also showed a consistent higher performance across different biological targets. Besides, it could correctly differentiate structurally similar ligands, indicating higher sensitivity to analogues. Collectively, the better performance of ID-Score enables it as a useful tool in assessing protein-ligand binding affinity in structure-based drug discovery as well as in lead optimization.

The Impact of Banana-Shaped Fragments on Trochanteric Hip Fractures Treated by PFNA.

Background: Regarding trochanteric hip fractures, one type of posterior coronal fragments was described as the "banana-shaped fragment", while the impact of the banana-shaped fragment on mechanical stability has not been further studied. The current study investigated the association between the banana-shaped fragment and mechanical complications after surgery. Methods: This retrospective cohort study included 273 patients treated by proximal femoral nail antirotation (PFNA) in the full analysis. The age, the sex, the fracture side, the follow-up time, the American Society of Anesthesiologists classification, the operators, the fracture classification, the tip-apex distance, the blade positions, the reduction quality and the bone mineral density were analyzed in relation to mechanical complications, through univariate and multivariate approaches. Results: Mechanical complications happened in 33 patients. The banana-shaped fragment (adjusted odds ratio 5.240, 95% CI 2.172 to 12.641; p < 0.001), the tip-apex distance and the reduction quality showed significant association with mechanical complications in both univariate and multivariate analysis. Moreover, for 118 patients with the banana-shaped fragment, we found that the use of wire cerclage couldn't significantly lower the rates of mechanical complications (p = 0.648). Conclusions: The banana-shaped fragment had a negative impact on mechanical stability of trochanteric hip fractures treated by PFNA. In the perioperative period, the BSF should be carefully evaluated, and its specific handling deserves further study.

Computational evaluation of the axis-blade angle for measurements of implant positions in trochanteric hip fractures: A finite element analysis.

BACKGROUND: Recently, a novel approach axis-blade angle (ABA) was developed to measure implant positions during trochanteric hip fracture surgery. It was defined as the sum of two angles α and ß measured between the femoral neck axis and helical blade axis in anteroposterior and lateral X-ray films, respectively. Although its clinical practicability has been confirmed, the mechanism is yet to be investigated by means of finite element (FE) analysis. METHODS: Computed tomography images of four femurs and dimensions of one implant at three angles were obtained to construct FE models. For each femur, 15 FE models in an arrangement (intramedullary nails at three angles multiplying five blade positions) were established. Under the simulation of normal walking loads, the ABA, von Mises stress (VMS), maximum/minimum principal strain and displacement were analyzed. RESULTS: When the ABA increased, all outcome indicators initially decreased till reaching inferior-middle site and then increased while the blade positions within the femoral head shifted from the superior-anterior quadrant toward the inferior-posterior quadrant, where the ABA were higher. Only the peak VMS of implant models in the inferior-posterior quadrant (particularly the inferior-middle site within) with blades in did not reach the yielding (risky) cut-off. CONCLUSIONS: From the perspective of angles, ABA, this study demonstrated the inferior-posterior quadrant as the relatively stable and safe regions, especially the inferior-middle site within. This was similar but more elaborate compared with previous studies and clinical practice. Therefore, ABA could be employed as a promising approach to anchor the implants into the optimal region.

Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor.

Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future.

Discovery of novel fatty acid synthase (FAS) inhibitors based on the structure of ketoaceyl synthase (KS) domain.

Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification.

RASA: a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules.

In this account, a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules, called RASA (Retrosynthesis-based Assessment of Synthetic Accessibility) is devised. RASA first constructs a synthesis tree for the target molecule based on retrosynthetic analysis; in this process a series of strategies are suggested for limiting combinatorial explosion of the synthesis tree. A scoring function (RASA-score) for the assessment of synthetic accessibility is then proposed based on the optional effective synthetic routes, the complexity of reaction, and the difficulty of separation/purification associated with the most favorable synthetic route. The contributions of individual components are calibrated by linear regression analysis based on the synthetic accessibility estimates of a training set (100 compounds) given by a group of medicinal chemists (G1). Two external test sets (TS1 and TS2), whose synthetic accessibility estimates were given by the group G1 medicinal chemists and another group (G2) of medicinal chemists (from literature), respectively, were adopted for the evaluation of RASA. The correlation coefficient between the calculated RASA-score values and the estimated scores by medicinal chemists for TS1 is 0.807 and that for TS2 is 0.792, which demonstrate the validity and reliability of RASA. The validity and reliability as well as the high speed of RASA and its capability of suggesting synthetic routes enable it a useful tool in drug discovery.

Discovery of novel Pim-1 kinase inhibitors by a hierarchical multistage virtual screening approach based on SVM model, pharmacophore, and molecular docking.

In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.

Using extended Wilson model to study the relationship between critical relative humidity and solubility of electrolytes.

Based on thermodynamic principle, the critical relative humidity of electrolytes is closely related to their solubility. The authors explored the relationship theoretically and calculated critical relative humidity of 21 electrolytes from their solubility in the light of Raoult's law and extended Wilson model. The results indicate that the critical relative humidity values calculated by Raoult's law can not accord with the reported ones and there is a systematic error in the high concentration range; while these calculated by extended Wilson model are comparable to the reported ones.

Pharmacophore modeling study based on known spleen tyrosine kinase inhibitors together with virtual screening for identifying novel inhibitors.

In this investigation, chemical features based 3D pharmacophore models were developed based on the known inhibitors of Spleen tyrosine kinase (Syk) with the aid of hiphop and hyporefine modules within catalyst. The best quantitative pharmacophore model, Hypo1, was used as a 3D structural query for retrieving potential inhibitors from chemical databases including Specs, NCI, MayBridge, and Chinese Nature Product Database (CNPD). The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking studies to refine the retrieved hits. Finally 30 compounds were selected from the top ranked hit compounds and conducted an in vitro kinase inhibitory assay. Six compounds showed a good inhibitory potency against Syk, which have been selected for further investigation.

Step nonisothermal method to study stability of drugs.

A step nonisothermal experiment under high oxygen pressure and a new computation with optimization for step nonisothermal experiment on stability study of drugs was introduced. The kinetics parameters of captopril oxidation in aqueous solution were determined by this method. It is reported that the reaction of captopril solution occurs under either aerobic or anaerobic condition, giving different products. Then the total rate constant k(total) can be expressed as [image omitted] where k(anaerobic) and k(aerobic) are the rate constants of anaerobic and aerobic degradations, respectively. The results indicated that the parameters obtained in the step nonisothermal experiment were comparable with those obtained in the isothermal-isobaric experiments. By a computer simulation, the estimates for the kinetic parameters (E(a) and k(0)) obtained with step nonisothermal method were statistically evaluated. Results indicated that the estimates obtained with isothermal-isobaric method were somewhat more precise than those obtained with step nonisothermal method. However, the experimental period needed by isothermal-isobaric method was much longer than that needed by step nonisothermal method.

Single time point isothermal drug stability experiments at constant humidity.

A single time point isothermal drug stability experiments at constant humidity is introduced. In the new method, kinetic parameters related to both moisture and temperature were obtained by a single pair of experiments: these related to moisture by one with a group of testing humidities and a fixed temperature, those related to temperature by the other with a group of testing temperatures and a constant humidity. By a simulation, the estimates for the kinetic parameters (E(a), m, A) obtained by the proposed method and the reported programmed humidifying and heating method were statistically evaluated and were compared with those obtained by the isothermal measurements at constant humidity. Results indicated that under the same experimental conditions, the estimates obtained by the proposed method were significantly more precise than those obtained by the reported programmed humidifying and heating method. The estimates obtained by the isothermal method at constant humidity were somewhat more precise than those obtained by the proposed method. However, the experimental period needed by the isothermal method at constant humidity was greatly longer than that needed by the proposed method. The stability of dicloxacillin sodium, as a solid state model, was investigated by the single time point isothermal drug stability experiments at constant humidity. The results indicated that the kinetic parameters obtained by the proposed method were comparable to those from the reported.

[Study of supercontinuum in nanofiber].

Using split-step Fourier transform method, the authors performed the simulation on supercontinuum generation (SCG) of femtosecond laser in nanofiber. The effects of diameter of the nanofiber, peak power and input pulse duration on the supercontinuum generation were analyzed. The results show that the higher the peak power of the input pulse, the easier the supercontinuum generation could be observed; the narrower the input pulse, the wider the light spectrum width. The dimension of the nanofiber plays an very important role in supercontinuum generaion of femtosecond laser pulse, the supercontinuum generation is not inversely proportional to the diameter of nanofiber, and there is a optimum diameter of nanofiber for the certain input laser pulse, so that the supercontinuum generation can be noteworthy. The obtained results in this paper would be helpful for further research on and making use of the supercontinuum generation in nanofiber.