132 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.

Provided are methods of using a compound that binds to interleukin- 1 beta (IL- 1β) at a binding pocket of IL- 1β identified herein, which traps the IL- 1β and inhibits its interaction with interleukin- 1 receptor type I (IL-1R1).

The invention provides an enzyme modification method based on artificial intelligence. The enzyme modification method comprises the following steps: training an AlphaFold2 model to obtain a glycosyltransferase tertiary structure prediction model; performing multi-sequence comparison on the protein and nucleic acid sequence database and the non-redundant protein feature sequence database based on the active point location recognition model to obtain a comparison result; initializing a matrix of which the length is equal to that of a comparison result, so as to construct a PSSM matrix and screen out potential mutation sites; according to the screened potential mutation sites, constructing an initial mutation library to form a virtual screening mutation library; performing structure reconstruction on the sequence in the virtual screening mutation library based on a glycosyl transferase tertiary structure prediction model so as to predict the glycosyl transferase tertiary structure and perform molecular docking and dynamic simulation on the glycosyl transferase tertiary structure; the method is used for analyzing binding pockets of proteins and ligands and determining dynamic interaction of amino acid residues and ligands in the binding pockets, and the contact number of each amino acid residue and the ligands is used for modifying the tertiary structure of the glycosyltransferase.

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 discloses a glutamate decarboxylase multi-site combined mutant and application thereof, and relates to the technical field of enzyme engineering and gene engineering. Amino acid residue sites needing to be mutated are determined on the basis of amino acid sites near key amino acids of a coenzyme 5 '-phosphopyridoxal binding pocket, and experimental verification is performed through a site-directed mutagenesis technology in combination with a high performance liquid chromatography screening method. Compared with a chemical synthesis method, the compound is synthesized by utilizing glutamic acid decarboxylase through biological catalysis, the synthesis condition is mild, the operation is simple, and separation and extraction are easy. According to the method, the screening probability of mutant amino acid sites can be effectively improved, the experiment efficiency and feasibility are improved, and the mutant enzyme of which the enzyme activity is obviously superior to that of the parent enzyme is obtained through screening.

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 a targeted regulation molecule and a regulation method for target protein conformation in living cells. The protein conformation targeting regulation molecule comprises: 1) a targeting group selectively combined with a target protein as a skeleton, 2) two active functional groups modified on the skeleton, and c) a rigid connecting arm introduced between the targeting group and the active functional groups. After being co-incubated with cells, the protein conformation targeted regulation molecule based on the characteristics can be rapidly and specifically combined with target protein in the cells through cell membranes, and is subjected to covalent reaction with amino acid near a binding pocket, so that the conformation of the target protein is regulated in a targeted manner. According to different protein conformations and different reaction sites, different active groups and rigid connecting arms are adopted to realize accurate regulation and control of target protein conformations in different functional states. The invention provides important technical support in the fields of exploration of protein conformation and functions, expansion of patent medicine protein libraries, research of new use of old medicines and disease treatment or prevention.

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 belongs to the technical field of enzyme engineering, and particularly relates to a terminal deoxynucleotidyl transferase mutant and application thereof, and the mutant is obtained by performing R189L / K191G mutation on any one of amino acid sequences as shown in SEQ ID NO.1-7. Starting from a truncated terminal deoxynucleotidyl transferase TdT derived from Zonotrichia albicola, 52 key residues located in a substrate binding pocket are fixed to obtain 7 terminal deoxynucleotidyl transferase mutant sequences, the unfolding temperature Tm of five of the 7 terminal deoxynucleotidyl transferase mutant sequences is 10 DEG C or above higher than that of wild type WT / LG, after the obtained mutants are subjected to heat treatment, the mutant sequences are separated from the wild type WT / LG, and the terminal deoxynucleotidyl transferase TdT is separated from the wild type WT / LG to obtain the 7 terminal deoxynucleotidyl transferase mutant sequences. According to activity characterization of the mutant, compared with a wild type, the mutant obtained by the invention can obviously enable a primer to extend, has higher product yield and can play an important role in DNA enzymatic synthesis.

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 provides a fused heterocyclic compound, a pharmaceutical composition and application thereof.The compound comprises a compound shown in the formula I: # imgabs0, the compound provided by the invention can be competitively combined with CLK2 in a targeted mode with ATP in a binding pocket of ATP of the CLK2, the compound shown in the formula I has an excellent CLK2 inhibiting effect, and the compound can be used as a medicine for inhibiting the CLK2. And the compound can be used for preventing and treating cancers related to CLK2 amplification or CLK2 overexpression.

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 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.

A total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed. The synthesis, achieved by the addition of two aryl chloride substituents to provide tetrachlorovancomcyin aglycon (Compound II), tetrachlorovancomcyin (Compound I ), and their derivatives, permitted a streamlined total synthesis of the new class of glycopeptide antibiotics by removing atropisomer stereochemical control and enabled the simultaneous and further activated SNAr macrocyclizations that establish the tricyclic skeleton of Compound I. In addition to the antimicrobial evaluation of tetrachlorovancomycin (Compound I), the preparation of key binding pocket and peripherally-modi fied derivatives, which overcome vancomycin resistance and introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for use of this new class of synthetic glycopeptide analogues. Also disclosed are a pharmaceutical composition containing bactericidal amount of tetrachlorovancomycin, a derivative thereof or a salt of either dissolved or dispersed in a pharmaceutically acceptable diluent.

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.

A total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed. The synthesis, achieved by the addition of two aryl chloride substituents to provide tetrachlorovancomcyin aglycon (Compound II), tetrachlorovancomcyin (Compound I ), and their derivatives, permitted a streamlined total synthesis of the new class of glycopeptide antibiotics by removing atropisomer stereochemical control and enabled the simultaneous and further activated SNAr macrocyclizations that establish the tricyclic skeleton of Compound I. In addition to the antimicrobial evaluation of tetrachlorovancomycin (Compound I), the preparation of key binding pocket and peripherally-modi fied derivatives, which overcome vancomycin resistance and introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for use of this new class of synthetic glycopeptide analogues. Also disclosed are a pharmaceutical composition containing bactericidal amount of tetrachlorovancomycin, a derivative thereof or a salt of either dissolved or dispersed in a pharmaceutically acceptable diluent.

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.

Provided is an amino acid recognition agent having improved binding properties, which is capable of obtaining more structural information from a polypeptide based on the kinetics of the on-off binding between the recognition agent and the polypeptide. The amino acid recognition agent may comprise an amino acid binding protein having an engineered binding pocket with one or more modifications relative to a homologous protein. Compared with an unmodified homologous protein binding pocket, the modified binding pocket can increase the number of interactions formed between the binding pocket and an amino acid ligand, and can increase the number of types of amino acid ligands capable of detecting binding compared with the unmodified homologous protein binding pocket. According to the present invention, the amino acid ligands of one or more types can be bound to one or more types of amino acid ligands, and can improve kinetics (e.g., KD, koff, kon) binding to one or more types of amino acid ligands, which advantageously increases the amount or confidence of structural information obtained from polypeptide analysis.