102 results about "Binding pocket" patented technology

The invention relates to the technical field of computer-aided drug design, in particular to a drug molecule screening and optimizing method based on artificial intelligence prediction, which comprises the following steps: S1, obtaining a dynamic protein conformation set and molecular multi-dimensional characterization: obtaining a dynamic conformation set of a target protein and a physicochemical property spatial distribution diagram of a binding pocket of the dynamic conformation set, a two-dimensional molecular map topological structure and three-dimensional conformation coordinates of the drug molecules are obtained; s2, multi-modal fusion prediction is carried out; s3, generating interpretable optimization guidance; and S4, automatic iterative optimization: performing batch prediction and screening on the new candidate molecular structure, taking the screened optimal molecule as a new starting point, repeatedly executing the interpretability optimization guidance generation step and the step until an iteration termination condition is met, and outputting a final optimized molecule list. Through the multi-modal fusion deep learning model, the interaction strength of the drug molecules and the target protein can be quickly and accurately predicted, and the screening efficiency of the drug molecules is greatly improved.

The present invention discloses a pectin methylesterase mutant ΔDdPemA, its encoding gene, preparation method, and application. The pectin methylesterase mutant ΔDdPemA is obtained by mutating the amino acid at position 200 in the center of the substrate binding pocket of the wild-type pectin methylesterase DdPemA from a high-molecular-weight, branched valine to a low-molecular-weight alanine, and by mutating the amino acid at position 339 at the substrate inlet and outlet of the substrate binding pocket from a high-molecular-weight, branched valine to a basic lysine. The amino acid sequence and nucleotide sequence of the wild-type pectin methylesterase DdPemA are SEQ ID NO. 1 and SEQ ID NO. 2, respectively. The mutant enzyme provided by the present invention has significantly improved enzyme activity under weakly acidic conditions, solving the problem of insufficient catalytic activity of the wild-type pectin methylesterase under weakly acidic conditions and creating favorable conditions for the application of the enzyme in the fields of food, textiles, and feed processing.

The invention belongs to the field of medical technology analysis, and discloses an analysis method and system for revealing a hidden binding pocket of a drug target, and the method comprises the steps: firstly obtaining a representative conformation metastable state of a target protein through conventional molecular dynamics simulation and clustering analysis; secondly, constructing a Markov state model to analyze a dynamic transformation rule between conformations; carrying out enhanced sampling by adopting meta-dynamics, and deeply exploring a rare conformation space; and finally, constructing a free energy landscape to quantitatively evaluate the relative stability of the conformation, and identifying a hidden binding pocket in the stable rare conformation. According to the method, the limitation of a single calculation means is overcome, a full-chain calculation system of dynamic conformation analysis-hidden cavity feature mining-novel ligand rational design is constructed, and the formation mechanism and potential druggability of the hidden pocket can be comprehensively revealed from the two dimensions of dynamics and thermodynamics; and an efficient and accurate calculation framework is provided for research and development of innovative drugs targeting difficult drug targets.

The invention relates to application of a DDX39B protein inhibitor in preparation of acute leukemia treatment medicines, and belongs to the technical field of biological medicines. In order to solve the problems of single acute leukemia treatment scheme and lack of novel medicines at present, the invention provides application of a DDX39B protein inhibitor in preparation of acute leukemia treatment medicines. Targeted inhibition of DDX39B can significantly hinder proliferation of leukemia cells, promote apoptosis and differentiation of cells, retard the process of cell cycles, delay disease progression in vivo and prolong the lifetime of model animals. On the basis of an RNA (Ribonucleic Acid) binding pocket structure of DDX39B, through high-throughput drug screening, the small molecule compound HMU-4051C is firstly identified as a DDX39B targeted inhibitor to effectively kill leukemia cells, and a new application of the DDX39B protein inhibitor in preparation of acute leukemia treatment drugs is developed.

The invention discloses a protein-ligand binding affinity prediction method and system based on structure perception, and belongs to the field of bioinformatics and drug research and development. In order to solve the problem of low accuracy of affinity prediction caused by neglect of structural modal information of a protein-ligand compound in the existing affinity prediction, the invention provides the affinity prediction method. The method comprises the following steps: performing integer coding on a protein sequence and a ligand SMILES character string to obtain a sequence predicted value; expressing the protein binding pocket-ligand compound as an isomeric graph, and encoding the protein-ligand compound isomeric graph to obtain predicted values corresponding to node features and edge features; on the basis of the isomerism graph, homographs are generated through two element paths of'protein atoms-ligand atoms-protein atoms' and'ligand atoms-protein atoms-ligand atoms', encoding is carried out according to the homographs of the element paths, fusion features corresponding to the two element paths are obtained, and then corresponding predicted values are obtained; and obtaining a final predicted value based on all predicted values.

The present invention discloses a method for predicting peptides that are capable of binding to HLA molecules that incorporate the crystal structure of HLA molecules. An improved HLA-specific peptide docking workflow is used to simulate the occupancy of a peptide on the binding pocket of an HLA molecule, and three models are trained to predict the binding of the peptide to HLA molecules. The results show that these models predict HLA-allele specific binding peptides with extremely high accuracy.

The invention relates to the technical field of medicinal chemistry, radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a CDK4 / 6-targeted molecular imaging probe labeling precursor, a probe and a preparation method and application thereof. According to the molecular imaging probe [68Ga] Ga-PY03 provided by the invention, on the basis of a Ribociclib structure, a PEG1 chain and proline with envelope conformation are introduced, so that a hydrophobic region in a protein binding pocket can be filled, Van der Waals force can be enhanced, the molecular imaging probe [68Ga] Ga-PY03 can be stably bound with CDK4 / 6, and the targeting of the molecular imaging probe to the CDK4 / 6 is further ensured; the hydrophilicity of the molecular imaging probe can be adjusted, and kidney uptake is reduced; and the compound has excellent tumor / liver and tumor / muscle ratio, and can effectively improve tumor uptake.

The invention provides a disease marker binding pocket identification method, and belongs to the technical field of disease marker binding pockets, and the method comprises the following steps: firstly, constructing a simulation system containing a disease marker, and carrying out 100-500ns molecular dynamics simulation; a conformation change track is collected and subjected to normalization processing; carrying out decomposition calculation on the sampled conformation, and analyzing a conformation cluster with relatively high frequency; calculating structural parameters of amino acid residues, and screening a region with relatively high flexibility as a potential binding site; analyzing the solvent accessibility and electrostatic characteristics of the sites; identifying a temporary binding pocket through the water molecule distribution density; performing principal component analysis to extract a conformation change mode; constructing an amino acid residue interaction network, and screening a stable binding pocket based on indexes such as binding free energy, conformational stability and pocket comprehensive performance evaluation; the method solves the problem that most existing methods only consider static structural characteristics of molecules and neglect the influence of dynamic change of protein conformation on binding pocket formation.

The invention belongs to the technical field of biological enzyme engineering, and particularly relates to a glucosamine-6-phosphate synthetase mutant and application thereof. A plurality of glucosamine-6-phosphate synthase mutants capable of remarkably improving the yield of N-acetylglucosamine are screened by performing single-point mutation or combined mutation on amino acid residues near a substrate binding pocket of the glucosamine-6-phosphate synthase or on the surface of protein of the glucosamine-6-phosphate synthase. According to the technical scheme, a foundation is laid for producing glucosamine by further transforming escherichia coli through metabolic engineering.

The application belongs to the technical field of bio-chemical industry, and particularly relates to a P450 enzyme mutant and application of an engineering bacterium thereof in synthesis of calcifediol, the mutant is one or more point positions in an amino acid sequence based on a wild type P450 enzyme Vdh being mutated; the amino acid sequence of the wild type P450 enzyme Vdh corresponds to GenBank accession number CP069288.1. Through systematic molecular dynamics simulation, conservation analysis and substrate binding pocket engineering on the Vdh enzyme, multiple key mutation sites are successfully screened and obtained. The constructed combined mutant (such as I114R / N173M / Q310R, Vdh-M3) shows extremely high hydroxylation activity, and the pure enzyme activity can reach 9.8 times of the wild type enzyme, greatly improving the conversion rate from vitamin D3 to calcifediol.

The invention discloses a sulfonylurea structure-containing compound as well as a preparation method and application thereof, and relates to the technical field of preparation and application of medical inhibitor compounds. The structure of the compound containing the sulfonylurea structure is shown in the specification. The preparation method comprises the following three steps: synthesizing an intermediate 1 from raw materials through Suzuki coupling reaction, obtaining an intermediate 2 through Sonogashira coupling reaction, and synthesizing a target compound through Williamson reaction. Through the synergistic effect of sulfonyl and ureido, accurate recognition and efficient embedding of a kinase ATP binding pocket are achieved, and the technical bottlenecks that a traditional c-Met inhibitor is poor in selectivity, drug resistance is likely to be generated and the synthesis process is complex are solved.

This invention relates to an antibacterial membrane-penetrating peptide and its applications. The amino acid sequence of the antibacterial membrane-penetrating peptide includes the sequence shown in SEQ ID NO.1 or a sequence with more than 70% homology to the sequence shown in SEQ ID NO.1. This invention screened and obtained a short peptide that specifically binds to the bacterial Hsp70s protein. It was found that this peptide binds to the Hsp70s protein through a traditional substrate-binding pocket, exhibiting an unusually high affinity for the protein in the DnaK-ATP state. The short peptide can inhibit Hsp70s protein activity to a certain extent, preventing it from aiding in the renaturation of denatured luciferase. Furthermore, while maintaining the integrity of the bacterial cell membrane, this short peptide has a superior ability to cross the bacterial cell membrane. The invention further discusses its application potential in the preparation of antibacterial drugs and antibiotic adjuvants, providing new ideas for solving current problems such as bacterial resistance and the difficulty in discovering new antibiotics.

The application discloses a drug design method and device based on topological data analysis, equipment and medium, relates to the technical field of computer-aided drug design, and the method comprises the steps of obtaining a plurality of three-dimensional structure conformations of a target protein, determining the binding pocket region of each three-dimensional structure conformation, and constructing a conformation set; calculating a topological descriptor representing the topological relationship between atoms based on the atomic coordinates of the binding pocket region of each three-dimensional structure conformation, and converting the topological descriptor into a corresponding conformation feature vector; performing a pooling operation on the conformation feature vector corresponding to each three-dimensional structure conformation to generate a unified topological feature representation representing the common topological feature mode of the target protein binding pocket under a plurality of three-dimensional structure conformations; and screening or generating candidate drugs based on the unified topological feature representation. The common topological invariant information of a plurality of conformations is used to represent the flexible protein binding pocket, the screening omission caused by single conformation representation is reduced, and the representation accuracy and the calculation efficiency are considered.

The present invention discloses a method for predicting drug-target affinity based on multi-shell and extended connectivity fingerprints, using protein-ligand complexes in the PDBbind database as a data set; modeling the binding pockets of macromolecular proteins and small molecule ligands, constructing N shells outward from the geometric center of the ligand, and mapping protein atoms to each shell according to the spatial coordinates of the protein atoms; classifying ligand atoms into multiple categories through features such as atomic symbols, explicit valences, etc.; taking all specific atom pairs as the features of this shell, and superimposing the features of multiple shells to obtain the feature vector of the complex; through 3D slicing of the complex features, using Transformer to learn the shell atom pair features. The present invention solves the problem that existing methods cannot characterize long-range interactions; through 3D slicing of the complex features, Transformer can well learn the shell atom pair features, thereby changing the performance of the characterization.

The invention belongs to the technical field of biochemical engineering, and particularly relates to application of a P450 enzyme mutant and engineering bacteria thereof in synthesis of calcifediol, and the mutant is obtained by mutating one or more sites in an amino acid sequence based on a wild type P450 enzyme Vdh; the amino acid sequence of the wild type P450 enzyme Vdh corresponds to the accession number of GenBank, namely CP069288.1. Through systematic molecular dynamics simulation, conservative analysis and substrate binding pocket engineering on the Vdh enzyme, a plurality of key mutation sites are successfully screened and obtained. The constructed combined mutant (such as I144R / N173M / Q310R, Vdh-M3) shows extremely high hydroxylation activity, the pure enzyme activity of the combined mutant can reach 9.8 times that of a wild type enzyme, and the conversion rate from vitamin D3 to calcifediol is greatly increased.

The invention discloses a mutant of glutamate dehydrogenase derived from clostridium symbiosum, and an application of the mutant in synthesis of L-glufosinate-ammonium, and particularly discloses a mutant of glutamate dehydrogenase derived from clostridium symbiosum and an application of the mutant in synthesis of L-glufosinate-ammonium. According to the invention, single-site or multi-site mutation is carried out on wild-type glutamate dehydrogenase derived from clostridium symbiotic as shown in SEQ ID NO.1 by virtue of a mutation transformation method which is designed by carrying out rational analysis on amino acid residues in a binding pocket of glutamate dehydrogenase and a substrate, a geometrical shape in a molecular tunnel and interaction of domains in a structural domain; according to the obtained single-site or multi-site mutant, the catalytic activity to 2-carbonyl-4-(hydroxymethylphosphonyl) butyric acid is remarkably improved, and the mutant has an application prospect in preparation of L-glufosinate-ammonium through biological catalysis.

The invention belongs to the technical field of molecular biology and drug screening, and provides a screening method of capsaicin targeting SOCS5-RBMX protein interaction and application of the capsaicin, an SOCS5-RBMX protein complex structure is analyzed, and SOCS5-RBMX binding structural domains and SOCS5-RBMX binding key sites are determined; the effect of inhibiting protein binding is verified through point mutation of the key sites; determining a binding pocket, taking a drug in the ZINC22 small molecule drug database and a drug approved by FDA as ligand molecules, and taking the binding pocket as a docking region for virtual screening to obtain a compound; the obtained compound is screened through AMDET, and the screened medicine for inhibiting SOCS5-RBMX binding is capsaicin; capsaicin is used for carrying out in-vivo and in-vitro experiments for further screening verification; according to the method, the structure of the SOCS5-RBMX protein complex is analyzed, the binding structural domain and the key site are determined, virtual screening and experimental verification are carried out on the basis of the binding structural domain and the key site, the medicine for inhibiting SOCS5-RBMX binding can be accurately screened out, and the accuracy and efficiency of medicine screening are improved.

The application belongs to the technical field of molecular biology and drug screening, and provides a method for screening phenylhydrazine sulfate based on a key binding amino acid site of SOCS5-CP and application thereof, which comprises the following steps: key amino acid sites of SOCS5-CP binding are screened through alanine virtual point mutation, and a binding pocket is determined; a ligand molecule is used to perform virtual screening by taking the binding pocket as a docking area, and a compound with the best binding energy is obtained; the obtained drug is screened through AMDET; the selected compound is used for subsequent in-vitro cell experiments, and further screening is performed; the application uses the method of molecular docking and virtual screening in combination with in-vitro experiments for screening, and finds that phenylhydrazine sulfate can be stably combined at the key amino acid sites of SOCS5-CP, in-vitro experiments show that phenylhydrazine sulfate can effectively inhibit the binding of SOCS5-CP, and further down-regulate the protein expression level of HIF1a in hepatoma cells, and also has a significant inhibitory effect on the invasion and migration ability of primary hepatocellular carcinoma.

The present invention discloses a method and device for recommending mutatable sites from small-sample experimental data, comprising the following steps: obtaining small-sample experimental data, including the sequences and data of wild enzymes and mutants, and obtaining the optimal mutant sequence according to the data type of the mutants; predicting the mutant structure based on the optimal mutant sequence; predicting the substrate-binding pocket based on the mutant structure; predicting single mutation sites based on the protein structure model, and selecting residues with a distance from the center of the substrate-binding pocket less than a first threshold as the recommended single mutation sites; selecting sites from the small-sample experimental data, mutating each site in the site set into 19 other amino acids, and pairwise combining them to construct a double mutation set, predicting the mutation results, and obtaining the recommended double mutation sites according to the sorting results; selecting sites from the small-sample experimental data, obtaining the coordinates of the sites in the variant structure for clustering analysis, and selecting 1 site from each cluster to combine with other clusters to construct multi-mutations; predicting the mutation results of the multi-mutations, and obtaining the recommended multi-mutation sites according to the sorting results; the method of the present invention operates effectively under the condition of small-sample data; through the powerful generalization ability of the large language model, the structural and functional information in biomolecules can be captured, so as to effectively encode the sequence of the enzyme for more accurate inference.

Provided herein, in certain aspects, are methods for inhibiting a TNFR1 -mediated activity using a compound that binds to a binding pocket of TNFR1 between CRD3 and CRD4 of TNFR1.

The invention discloses a biosensor responding to beta-alanine and application, and belongs to the technical field of bioengineering. A ligand binding pocket residue of BsGabR is subjected to mutation modification on the basis of a GABA biosensor, a BsGabR mutant capable of specifically recognizing and responding to beta-alanine and activating reporter gene expression is obtained through screening and iterative combinatorial mutation, the mutant is used for constructing a new biosensor, pregabalin can be efficiently and specifically responded, and the biosensor has a good application prospect. The method can be used for dynamic regulation and control of an amino acid metabolic pathway and a high-throughput screening platform of amino acid synthetase or strains, and has a relatively great application prospect.

The invention relates to the field of biological medicine and ophthalmic diseases, in particular to a target protein inhibitor for preventing and treating proliferative diabetic retinopathy and a screening method and application of the target protein inhibitor. The screening method comprises the following steps: 1) obtaining a three-dimensional crystal structure of CTSH; 2) constructing a binding pocket at an active site; 3) performing molecular docking and scoring on the small molecule library, and screening candidate compounds with binding energy lower than a preset threshold value; and 4) performing molecular dynamics simulation on the candidate compound and the CTSH compound, and selecting a compound with a stable structure and low binding free energy as an inhibitor. The inhibitor obtained by screening comprises eriodictyin, polygala tenuifolia sucrose ester B or an AP-III-a4 inhibitor. Genetic causal inference proves that CTSH has a causal driving effect on PDR, inflammation and pathological angiogenesis can be remarkably inhibited by regulating CTSH expression under a high glucose condition, and effective inhibitor components are finally screened.

The present application relates to a kind of target protein conformation targeting regulatory molecules and regulatory methods in living cells.The protein conformation targeting regulatory molecules include: 1) with the targeting group of selectively binding target protein as skeleton, 2) two active functional groups are modified on the skeleton, c) rigid connecting arm introduced between targeting group and active functional group.Based on the above characteristics, after the protein conformation targeting regulatory molecules of the cell are incubated with cell, they are rapidly combined with target protein in cell specifically through cell membrane, and covalent reaction occurs with amino acid near binding pocket, to target the conformation of target protein is regulated.According to the difference of protein conformation and reaction site, different active groups and rigid connecting arm are used, to realize the accurate regulation of target protein conformation in different functional states.The present application provides important technical support in the field of exploring protein conformation and function, expanding the library of druggable proteins, researching new use of old drugs, disease treatment or prevention.

The invention discloses a method for screening a small molecule compound capable of regulating and controlling brown adipose differentiation from ginsenoside and application of the small molecule compound. The present invention identifies a novel binding pocket in PPAR [gamma]-LBD. Through molecular docking, the Ginsenoside Rg3 is obtained by screening a plurality of ginsenosides, and experiments prove that the Ginsenoside Rg3 has relatively low toxicity to adipose-derived stem cells (ADSC) and can be used for remarkably activating an ADSC browning process at the same time.

The present application belongs to the field of bionic technology, and particularly relates to a kind of bionic material loaded with YD monomer and its preparation method and application.The present application utilizes YD monomer composed of tyrosine (Y) and aspartic acid (D) to synthesize a kind of bionic material through reversible addition-fragmentation chain transfer (RAFT) polymerization. The bionic material can produce spatially adjacent binding pockets through the covalent bond of tyrosine (Y) and aspartic acid (D), and can capture two kinds of PTM (phosphopeptide and O-glycopeptide) simultaneously through synergistic interaction. The results of the present application show that the bionic material of YD monomer optimizes charge balance, the neutral phenolic group of Y (pKa ~ 10) and the negatively charged carboxylate of D (pKa ~ 3.9) together reduce the electrostatic repulsion with phosphopeptide, while maintaining target affinity; self-assembled into nanostructured porous framework can expose multivalent binding sites, and significantly improve capacity and selectivity through synergistic effect.

The present disclosure relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein Ring A, G1, RC, X, RD1, RD2, and RD3 are as described herein, methods of preparation and intermediates useful in said preparation, methods of treatment and prevention (e.g., of Caspase-4 mediated diseases and disorders), and pharmaceutical compositions comprising same. Compounds of Formula (I), and pharmaceutically acceptable salts thereof, are designed as selective Caspase-4 allosteric inhibitors, sparing Caspase-1, and have also been found to be selective against Caspase-5 and are thus, in embodiments, considered dual Caspase-4 / 5- inhibitors. The present disclosure further relates to the Applicant's discovery of a new and allosteric human Caspase-4 binding pocket, and methods of binding to (and compounds inhibiting the activity of) same, methods of treatment and prevention, and pharmaceutical compositions comprising such compounds.

The application relates to the field of biological medicines, and discloses a method for screening a TRPM8 antagonist, which comprises the following steps: step 1, contacting a candidate substance with a TRPM8 protein or a functional fragment thereof, wherein the TRPM8 protein or the functional fragment thereof at least contains 796D, 861Q and 862R amino acid residues; step 2, detecting whether the candidate substance is specifically combined with at least one residue in the TRPM8 protein or the functional fragment thereof; and step 3, if combined and at the same time can produce an allosteric effect on the protein, it can be preliminarily judged that the candidate substance is a TRPM8 antagonist. The application fills the gap of the existing technology about the TRPM8 binding mode and the screening method by disclosing the key residues and the allosteric binding pocket of the TRPM8 protein combined with the antagonist, and promotes the clinical application transformation of the TRPM8 antagonist in the fields of neuropathic pain, antitumor and bone repair.

The invention relates to lactoferrin as well as a preparation method and application thereof, the lactoferrin is deferrited lactoferrin subjected to methylacryloylation treatment, and the number of heme binding sites on the lactoferrin is 7-13. When in use, the lactoferrin is prepared into a solution or prepared into hydrogel for injection and is used for being combined with free heme; the number of binding sites of the heme on the lactoferrin is 7 to 13; the lactoferrin is lactoferrin subjected to methacrylation treatment. According to the method, the number of pockets for binding the lactoferrin subjected to methacrylation treatment to the heme is increased, and the affinity to the heme and the binding capacity are remarkably improved.

Disclosed is a method of producing a non-naturally occurring peptide for reducing nitrogen, the method comprising: a) identifying a first group of peptides each having a binding pocket similar to a naturally occurring iron-sulfur cluster cofactor binding pocket of a naturally occurring nitrogenase, wherein each of the first group of peptides is not a nitrogenase or a subunit or domain of a nitrogenase; b) selecting, from the first group of peptides, a second group of peptides each having at least one target amino acid in the binding pocket; c) selecting, from the second group of peptides, a third group of peptides each having at least one target property; and d) modifying the sequence and / or structure of each of the third group of peptides to improve binding of the iron-sulfur cluster cofactor in the binding pocket. Also disclosed is a non-naturally occurring peptide for reducing nitrogen, comprising: at least one modification to a naturally occurring peptide; and a binding pocket for binding an iron-sulfur cluster cofactor; wherein the naturally occurring peptide is not a nitrogenase or a subunit or domain of a nitrogenase; and wherein the at least one modification improves binding of the iron-sulfur cluster cofactor in the binding pocket.

The present application belongs to the technical field of biotechnology and enzyme engineering, and relates to a molecular modification method for improving substrate specificity of aldehyde ketone reductase, which is achieved by constructing a substrate library of aldehyde ketone reductase AKR13B3 and analyzing kinetic parameters, determining a mutation site by performing loop structure analysis and amino acid sequence alignment on a complex structure of aldehyde ketone reductase AKR13B3, coenzyme NADPH and substrate 3-keto-DON, and screening a mutant with increased substrate specificity, the present application designs the geometric shape of the entrance loop region of the substrate binding pocket of AKR13B3 to change substrate preference and realize the increase of catalytic activity of the enzyme on specific substrates, in addition, the present application provides a feasible scheme for designing aldehyde ketone reductase with good substrate specificity, and provides great hope for developing high-efficiency enzyme preparations.