Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

Mutation Genes in Common Tumors of Digestive System and Druggability of New Targets / 肿瘤防治研究

Objective To establish a druggability evaluation method for new targets of anti-tumor drugs by analyzing the mutation genes of common tumors in the digestive system. Methods We collected the mutant gene data of the five common tumors of the digestive system (esophageal cancer, gastric cancer, colorectal cancer, liver cancer and pancreatic cancer) in the Integrative Onco Genomics database, and screened out the genes with higher mutation rates in each tumor. We evaluated the druggability of these genes or their encoded proteins, and discovered the potential targets for the new anti-tumor drugs. Results A total of five tumors, 35 cohorts and 5445 tumor samples were collected in this study. The top 10 mutation genes were selected for further analysis. The canSAR database was used to analyze the druggability of unpublished mutant genes or their encoded proteins, and a total of 17 potential therapeutic drug targets were screened out. Conclusion A method for evaluating druggability of targets based on mutant genes or their encoded protein is established in this study. The application of this method can provide a reference for discovering new anti-tumor therapeutic target, saving the cost and time of target screening in new drug development.

Determination of plasma protein binding of peptide drug candidates by dextran-coated charcoal / 中国药科大学学报

@#The conventional equilibrium dialysis and ultrafiltration methods cannot be used to determine the protein binding of some peptides because of their non-specific adsorption on the semipermeable membrane or poor stability in the plasma. The method of dextran-coated charcoal adsorption combined with LC-MS/MS were used. Based on the kinetic principle of initial rate of candidate drugs absorbed to dextran-coated charcoal, seven phosphorylated peptides with the same amino acid sequence and different configurations in rat plasma were selected as the study model using; the protein binding in rat plasma were determined; the amino acid distribution rules affecting the changes in protein binding rates of peptide candidate drugs were summarized. The results suggest that the dextran charcoal adsorption method, as a supplementary method for the determination of plasma protein binding, is suitable for peptides or organic drug candidates that cannot be determined by traditional techniques.

Research progress on macrophage membrane nano-biomimetic preparations on brain diseases and its inspiration on druggability of active components of traditional Chinese medicine / 中草药

Although nano preparations could improve the physicochemical properties of drugs, they are easy to be recognized and cleared by mononuclear phagocytes, which will not only reduce the half-life of drugs, but also cause immunogen reaction, thus affecting the safe and effective use of drugs. The combination of cell membrane and new nanotechnology will increase the cell compatibility with the advantages of nano preparations, further enhance the targeting effect of target organs or tissues, and improve the efficacy. At present, the existence of the brain barrier restricts the entry of all macromolecular substances and 98% small molecule drugs into the brain, becoming the main problem in the treatment of encephalopathy. Macrophages are common immune cells and play an important role in the development and prognosis of brain diseases. Therefore, the combination of macrophage membranes and nano preparations becomes the immune system's own substances to avoid recognition and clearance, and increase the circulation of drugs, then reuse the blood-brain barrier permeability of macrophages to increase the drug into brains to improve the clinical efficacy. Traditional Chinese medicine has complex components and significant curative effect, but most of them have problems in poor solubility and stability, which lead to low bioavailability in vivo and affect the application. Therefore, based on domestic and foreign literatures, this article integrates the application of macrophage membrane modified nano-preparations in encephalopathy and its effects on the medicinal properties of active ingredients of traditional Chinese medicine, in order to promote the development and utilization of traditional Chinese medicine resources.

mV, respectively, and the encapsulation efficiency and drug loading content were 87.9% and 0.57%. The final concentration of LM was 63.4 μg/mL. The release results showed 58.59% drug was released in 12 h. MTT results showed that the IC50 of LM@Lip on HepG2 and A549 cells was 20.16 and 15.39 μg/mL, respectively, and its in vitro antitumor was superior to that of LM. Conclusion Liposomes can increase the stability and solubility of LM. LM@Lip showed slow-release profile and significant tumor inhibition superior to LM. Key words: limonin; liposomes; thin-film dispersion method; orthogonal experiment; in vitro release; antitumor; druggability / 中草药

Objective: In view of druggability issue of limonin (LM), the liposomal preparation was developed. The liposomal formulation and preparation process were optimized, and its in vitro antitumor activity was investigated. Methods: In this study, LM was loaded in liposomes to increase its stability and solubility. Meanwhile, in vitro cytotoxicity of LM@Lip was evaluated. LM@Lip were prepared by thin-film dispersion method, and formulation selection and process optimization were operated by single factor and orthogonal experiment. Size distribution, PDI and zeta potential were measured by Malvern sizer, and the encapsulation efficiency and drug loading content were determined by HPLC. The dialysis method was used to investigate the release profile of LM@Lip. In vitro cytotoxicity against HepG2 and A549 cells were estimated by MTT method. Results: The optimized preparation conditions of liposomes were as follows: drug/lipid ratio was 1:150, cholesterol/lipid ratio was 1:9, the ultrasonic power was 120 W for 6 min (1 s interval). The average particle size, PDI and Zeta potential of optimized LM@Lip were (119.5 ± 6.2) nm, 0.318 ± 0.124, (-17.2 ± 1.3) mV, respectively, and the encapsulation efficiency and drug loading content were 87.9% and 0.57%. The final concentration of LM was 63.4 μg/mL. The release results showed 58.59% drug was released in 12 h. MTT results showed that the IC50 of LM@Lip on HepG2 and A549 cells was 20.16 and 15.39 μg/mL, respectively, and its in vitro antitumor was superior to that of LM. Conclusion: Liposomes can increase the stability and solubility of LM. LM@Lip showed slow-release profile and significant tumor inhibition superior to LM.

Efficient discovery and medicinal research of marine natural products / 中草药

Marine natural products (MNPs) are the source of modern marine drugs, but they have the characteristics of strong guiding function and weak druggability. How to quickly and efficiently discover new bioactive MNPs and optimize their druggability is an important idea for the research and development of innovative marine drugs. This article has made some discussions and suggestions on this emphasis from the origin and characteristics of MNPs, marine microorganisms with specific productivity for MNPs and the strategies of microbial MNPs with high yields and diverse structures, as well as the structural modification for medicinal use of MNPs.

Interpretation of Prescription and Syndrome of Yangjing Zhongyu Tang and Its Modern Research Progress / 中国实验方剂学杂志

Yangjing Zhongyu Tang, from FU Qing-zhu Nvke, is a famous classical formula of clinical value for treating blood deficiency syndrome of female infertility in the Qing dynasty. The prescription seems plain, but it is rigorous and effective with high research value. In this paper, the ancient books and modern documents of Yangjing Zhongyu Tang were analyzed from the aspects of traceability of Chinese materia medica in the formula, pharmacological research, clinical research, etc. It could be concluded that the pharmacological studies of this formula were mostly to investigate the mechanism and efficacy of its treatment for infertility, but there was a lack of comprehensive interpretation of the structure, function and principle of pharmacodynamic substance in this formula. In this paper, combined with the contents of supramolecular imprinting template and network pharmacology, the new direction of pharmacological research of Chinese medicine compound was put forward. Quality control of Yangjing Zhongyu Tang mostly based on small molecule compounds, so it was suggested to break the inherent thinking, and increase the detection of macromolecule compounds and supramolecular of Chinese materia medica. The druggability of this formula involved in the preliminary study of decoctions, plasters and granules. Considering the quality stability of Chinese materia medica in the formula and the scientificity of druggability of this formula, the compatibility principle of traditional Chinese medicine (TCM) and modern supramolecular chemistry theory could be combined to study the change law of druggability of TCM before and after compatibility, so as to provide new reference materials for the follow-up clinical application and development of Yangjing Zhongyu Tang.

Druggability and preparation modification of Chinese materia medica based on supramolecular “imprinted template” / 中草药

Chinese materia medica (CMM) is a multi-component system. In addition to the study on single-component druggability, the focus should be also on how to integrate the rules of single-component druggability to construct a research system of suitable multi-component druggability of CMM. According to the basic theory of CMM guidance, the druggability of CMM has been accumulated by long-term clinical practice experience, and the curative effect is affirmed. The most critical issue is how to determine the attribution and intermolecular interaction of the well-defined CMM component group and develop a component CMM. However, how to integrate the physicochemical and biological apparent properties of the multi-component based on the apparent physical and chemical properties of the single-component is the key to the study on druggability and preparation modification of CMM. Therefore, the druggability study of the single-component medicine and the study of the change rules of multi-component CMM druggability by using compatibility principle of CMM and modern supramolecular chemistry theory are needed to performed to study on the druggability of CMM. The combination of CMM druggability, preparations and chemical modifications can maximize the success rate of the development of new CMMs. The characteristic of the autonomous “Qi-xi” for CMM “imprinting template” of supramolecules has an important guiding role in druggability research of CMM both in theory and practice.

Application of nanotechnology in improving druggability of active ingredients of Chinese materia medica / 中草药

Nanotechnology has broad prospects and great potential in improving the druggability of active ingredients of Chinese materia medica (CMM). This article systematically summarized the methods and advantages of nanotechnology in improving oral absorption, changing the distribution in the body, increasing the targeting ability, and improving transdermal and mucous membrane absorption of active ingredients of CMM. In addition, we analyzed the problems in the development of improving the druggability of active ingredient of CMM by nanotechnology, put forward the strategies for solving these problems, and discussed the research prospects.

Synthesis and druggability study of triptolide stearate / 药学实践杂志

Objective To synthesize a lipophilic prodrug of triptolide (TP) and improve its druggability .Methods Trip-tolidestearate (TP-SA)was synthesized via the DMAP-catalyzed DCC method and identified by MS ,1H-NMR and 13C-NMR. The shake-flask method was used to study the oil/water partition coefficient .The preparations of TP and TP-SA liposomes and emulsions were compared .Their encapsulation efficiency and stability were investigated .Results TP-SA was synthesized suc-cessfully .Its log P in octanol/water system was 2 .33 .It was difficult to prepare TP liposome or emulsion .By contrast ,TP-SA liposome and emulsion can be prepared successfully with the same formulation process .The particle size of TP-SA lipo-somes were about 90 nm and TP-SA emulsions were about 110 nm .The encapsulation efficiency was above 95% .Their stabili-ty were studied at 4℃ and 25℃ .The preparation parameters ,such as particle size and encapsulation efficiency ,had no signif-icant change in a week .Conclusion Triptolide stearate enhanced drug lipophilicity .Its druggability was improved significant-ly .These data can be used for the TP related drug design and development .

Study on Pharmacological Key Problems of Druggability Evaluation for Novel Chinese Materia Medica / 世界科学技术-中医药现代化

The research and development (R & D) of novel Chinese materia medica (CMM) have made a great progress in recent years.But problems still exist in druggability evaluation of novel CMM,such as uncertain evaluation content and lack of key technology.Druggability evaluation is the key to the success or failure for R & D of novel CMM.Observation on the effect and safety of novel CMM is the core of druggability evaluation.The important pharmacological problems include the choice of evaluation indicator,clinical indication,analysis of material basis,investigation of mechanism,research on pharmacokinetics and safety evaluation.Modem technologies should be used in druggability evaluation.We should have a correct understanding of the concept of novel CMM.The grasp of the meaning of novel drugs and the essence of CMM theory will be helpful for R & D of novel CMM.

Applications of glycosyltransferases in the improvement of druggability of natural products / 中国药科大学学报

Natural products are one of the most important sources for druggable lead compounds given their diverse structures and activities.Nevertheless,very few of them can be directly developed to drugs.The undesirable druggability of natural products result from their weaker activity,lower aqueous solubility and poorer stability.Since improving druggability by chemical modifications is restricted by the limited access to the complex structures of natural products,enzymatic modification has gradually become one of important tools for the structural modification of natural products.Meanwhile,since enzymatic glycosylation by glycosyltransferases has shown certain advantages such as excellent regio-and stereo-selectivity,high catalytic efficiency and mild conditions.It has been a promising route for the improvement of druggability for natural products.In the present review,we summarize different glycosyltransferases and their application for structural modification of natural products as well as the challenges issues involved in the glycosylation,which provides a general perspective on the enzymatic modification of natural products for the improvement of their draggability.

Analysis on Druggability of Chinese Materia Medica and Its Relationship with Major New Drug Innovation and Development / 世界科学技术-中医药现代化

Druggability is crucial in pharmaceutical drug development as the source of drug research. Druggability research will face greater challenges because Chinese materia medica (CMM) is the multicomponent drug. In this paper, ideas and methods of study on CMM druggability were mainly proposed in combination with the chemical material basis of muticomponents of CMM.

Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus

The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present. Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus. The in-depth analysis of the viral protein to find the binding site, active pocket is needed. Here, the authors analyzed the envelope glycoprotein GP2 from Ebola virus. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus was done. According to this assessment, 7 active pockets with varied druggability could be identified.

Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus

The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present. Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus. The in-depth analysis of the viral protein to find the binding site, active pocket is needed. Here, the authors analyzed the envelope glycoprotein GP2 from Ebola virus. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus was done. According to this assessment, 7 active pockets with varied druggability could be identified.

Evaluation of effectiveness-cytotoxicity correlation and optimization of druggability for activity-based poisonous Chinese materia medica with antitumor activity / 中草药

The antitumor activity of the constituents from poisonous Chinese materia medica (CMM) is very strong, but mainly mediated by their unforeseeable cytotoxic effects, which results in increasingly prominent security issues in clinic. To improve the druggability of these drugs, it is urgent to put much attention on the effectiveness-cytotoxicity correlation study. Activity-based protein profiling can realize the discovery of pharmacological and cytotoxic information and drug design under the guidance of chemicals activity. In view of the promiscuity of natural chemicals, we utilize the method of comparative targets profile to calculate and seek druggable targets in biological networks for drug structure optimization. In conclusion, we take the loop mode of drug→disease→target→drug method, hoping to provide the reference for the research and development of new drug with high efficiency and low toxicity from poisonous CMM.