摘要：Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology,the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical *** to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence(AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening,activity scoring, quantitative structure-activity relationship(QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity(ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability,deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules,which will further promote the application of AI technologies in the field of drug design.

摘要：The evolution of glucocorticoid drugs was driven by the demand of lowering the unwanted side effects, while keeping the beneficial anti-inflammatory effects. Potency is an important aspect of this evolution as many undesirable side effects are associated with use of high-dose glucocorticoids. The side effects can be minimized by highly potent glucocorticoids that achieve the same treatment effects at lower doses. This demand propelled the continuous development of synthetic glucocorticoids with increased potencies, but the structural basis of their potencies is poorly understood. To determine the mechanisms underlying potency, we solved the X-ray structures of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to its endogenous ligand, cortisol, which has relatively low potency, and a highly potent synthetic glucocorticoid, mometasone furoate (MF). The cortisol-bound GR LBD revealed that the flexibility of the C1-C2 single bond in the steroid A ring is primarily responsible for the low affinity of cortisol to GR. In contrast, we demonstrate that the very high potency of MF is achieved by its C-17α furoate group completely filling the ligand-binding pocket, thus providing additional anchor contacts for high-affinity binding. A single amino acid in the ligand-binding pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol. Structure-based design led to synthesis of several novel glucocorticoids with much improved potency and efficacy. Together, these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing novel highly potent glucocorticoids.

摘要：The secretion of melatonin(MT)is obviously different in the younger and the senior sectors of the population,and the maximum plasma concentration of seniors is only half of that in the younger population *** exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system(DDS),an improved therapeutic effect and reduced side effects can be *** upon this hypothesis,the pharmacokinetic parameters of MT,namely,the absorption rate constant(ka),the elimination rate constant(ke),and the ratio of absorption rate(F)to the apparent volume of distribution(V)were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger *** dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system(DDS)to generate plasma MT profiles similar to the physiological level-time *** in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates,namely,4.919μg/h during 0-4 h(r=0.9992),and 11.097μg/h during 4-12 h(r=0.9886),*** the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors,an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger *** high similarity between the experimental drug release profiles and the theoretical profiles(similarity factor f_(2)>50)and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles(r=0.9366,0.9163,0.9264)ind

摘要：An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity.A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human *** discovered a novel cancer immunostimulant,trichosanthin(TCS),that is a clinically used protein drug in China,and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide,TCS,and a cell-penetrating peptide(CPP),termed an"allin-one"vaccine,for transcutaneous cancer *** TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor *** vaccines were prepared via a facile recombinant *** vaccines induced the maturation of DCs that subsequently primed CD8^(+)T *** TCS-based immunostimulation was associated with the STING *** general applicability of this genetic engineering strategy was demonstrated with various tumor antigens(i.e.,legumain and TRP2 antigenic peptides)and tumor models(i.e.,colon tumor and melanoma).These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving,and demonstrates the adjuvant application of TCSdan old drug for a new application.

摘要：The development of solid-state materials with switchable luminescence in response to stimuli remains a challenge,especially for organic *** crystal water significantly impacts the absorption spectra of organic crystals,it is unclear whether the emission spectra of organic luminescent materials can be systematically manipulated by *** this study,we successfully obtained curcumin monohydrate(Form X),a channel-type hydrate exhibiting crystallization-induced emission(CIE)at 608 nm(orange fluorescence),which contrasted with the conventional forms of aggregation-caused quenching(ACQ).Thermal treatment induced the release of hydration water,resulting in a new anhydrate(Form IV)that emitted yellow-green fluorescence with the emission peak at 575 ***,this approach can be used to track the absorption of curcumin crystals following subcutaneous or intramuscular *** hydratemediated single-crystal-to-single-crystal transition(SCSC)and its associated luminescence transition were reversible and responsive to temperature,offering a green approach for synthesizing and designing aggregation-induced-emission(AIE)-based intelligent luminescent devices for detecting air humidity or drug absorption.

摘要：Ginsenosides, the main pharmacologically active natural compounds in ginseng （Panax ginseng）, are mostly the glycosylated products of protopanaxadiol （PPD） and protopanaxatriol （PPT）. No uridine diphosphate glycosyltransferase （UGT）, which catalyzes PPT to produce PPT-type ginsenosides, has yet been reported. Here, we show that UGTPgl, which has been demonstrated to regio-specifically glycosylate the C20-OH of PPD, also specifically glycosylates the C20-OH of PPT to produce bioactive ginsenoside FI. We report the characterization of four novel UGT genes isolated from P. ginseng, sharing high deduced amino acid identity （〉84%） with UGTPgl. We demonstrate that UGTPgl00 specifically glycosylates the C6-OH of PPT to produce bioactive ginsenoside Rhl, and UGTPgl01 catalyzes PPT to produce F1, followed by the generation of ginsenoside Rgl from FI. However, UGTPgl02 and UGTPgl03 were found to have no detectable activity on PPT. Through structural modeling and site-directed mutagenesis, we identified several key amino acids of these UGTs that may play important roles in determining their activities and substrate regio-specificities. Moreover, we constructed yeast recombinants to biosynthesize F1 and Rhl by introducing the genetically engineered PPT-producing pathway and UGTPgl or UGTPgl00. Our study reveals the possible biosynthetic pathways of PPT-type ginsenosides in Panax plants, and provides a sound manufacturing approach for bioactive PPT-type ginsenosides in yeast via synthetic biology strategies.

摘要：Dear Editor,Ginseng has been traditionally used as herbal medicine in Asia for thousands of years to enhance physical performance and to increase resistance to stress and aging,and has been developed into various kinds of dietary supplement with increasing market demand [1].Its active constituents are ginsenosides,a group of triterpene saponins (ca.2％ in Panax ginseng dried roots) [1].However,the main functional component detected in mammalian blood or organs after oral administration of ginseng or ginsenosides is compound K (CK) [2],which presents bioactivities of anti-inflammation,hepatoprotection,antidiabetes and anti-cancer in experiments of in vitro cell biology and/or in vivo animal models (Supplementary information,Table S1).Recently,CK was approved by the China Food and Drug Administration to commence clinical trials (CDEL20130379) for arthritis prevention and treatment.

摘要：Nucleocapsid(N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), including the formation of ribonucleoprotein(RNP) complex with the viral *** we reported the crystal structures of the N-terminal domain(NTD) and C-terminal domain(CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.

摘要：The hydrogenation of CO_(2) into methanol has attracted much attention and In_(2)O_(3) is a promising *** metal elements into In_(2)O_(3)(M/In_(2)O_(3))is one of the main strategies to improve its ***,its mechanism and active sites remain unclear and need to be further ***,the noble‐metal‐free In_(x)‐Co_(y) oxides catalysts were ***‐improved performance and obvious product selectivity shift were *** optimized catalyst(In_(1)‐Co_(4))(9.7 mmol g_(cat)^(–1) h^(–1))showed five times methanol yields than pure In_(2)O_(3)(2.2 mmol g_(cat)^(–1) h^(–1))(P=4.0 MPa,T=300°C,GHSV=24000 cm^(3)_(STP) g_(cat)^(–1) h^(–1),H_(2):CO_(2)=3).And the cobalt‐catalyzed CO_(2) methanation activity was suppressed,although cobalt was most of the metal *** unravel this selectivity shift,detailed catalysts performance evaluation,together with several in‐situ and ex‐situ characterizations,were employed on cobalt and In‐Co for comparative *** results indicated CO_(2) hydrogenation on cobalt and In‐Co catalyst both followed the formate pathway,and In‐Co reconstructed and generated a surface In_(2)O_(3)‐enriched core‐shell‐like structure under a reductive *** enriched In_(2)O_(3) at the surface significantly enhanced CO_(2) adsorption capacity and well stabilized the intermediates of CO_(2) ***_(2) and carbon‐containing intermediates adsorbed much stronger on In‐Co than cobalt led to a feasible surface C/H ratio,thus allowing the*CH_(3)O to desorb to produce CH_(3)OH instead of being over‐hydrogenated to CH_(4).