40 results about "Druggability" patented technology

According to the GPX4 protein degradation agent and the application, the degradation agent serves as molecular glue to induce tumor cell ferroptosis and is different from an existing PROTAC technology, and the molecular glue can induce interaction between E3 ubiquitin ligase and target protein GPX4 and promote ubiquitination of the E3 ubiquitin ligase and the target protein GPX4. Compared with the existing GPX4 degradation agent, the molecular glue has the advantages of small molecular weight, high cell permeability and better druggability. The GPX4 molecular glue disclosed by the invention can be used for effectively degrading GPX4 and has a killing effect on various tumor cell lines. The preparation method is simple in synthesis route and mild in reaction condition, can be used for being developed into a new generation of GPX4 targeting drugs, and has great clinical application value and considerable market potential.

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 discloses a lead compound optimization method and system based on skeleton constraint and training enhancement, and belongs to the field of artificial intelligence drug discovery. The method comprises the following steps: performing structural treatment on an initial lead compound, extracting a growth skeleton structure, and pairing a protein pocket structure; inputting information of the skeleton structure and the protein pocket structure into a coding model based on a three-dimensional graph neural network for joint coding to obtain structure coding representation; on the basis of a Delete model, an atomic distance-based resampling mechanism and a hydrophobic group mask are introduced, and a molecular generation model is constructed; training and tuning a molecule generation model through staged pre-training and a knowledge enhancement fine tuning strategy so as to improve the structural accuracy, the binding activity and the druggability of generated molecules; and inputting the structure coding expression into a trained and optimized molecular generation model PocketGrow to generate optimized molecules, screening the generated optimized molecules, and outputting a lead compound with development potential.

The invention relates to the field of drug discovery and delivery collaboration, in particular to an autonomous evolutionary drug discovery and delivery collaboration method and system based on a large language model. The method comprises the following steps: aiming at a given biological target three-dimensional structure, generating a candidate molecular library which is complementary with a target pocket and gives consideration to druggability through an SE (3) isovariant hybrid generation model; according to a two-stage funnel type high-throughput virtual screening process, screening out the molecule with the highest comprehensive potential from the candidate molecule library; generating a customized delivery scheme through a three-stage process; in a digital twinborn model for simulating a real in-vivo tumor microenvironment, a targeted delivery process of a drug and carrier complex is simulated, and efficiency is evaluated; atomic-scale performance confirmation is carried out on a medicine, carrier and target point ternary system through molecular dynamics simulation. The invention is suitable for drug research and development.

The invention relates to the technical field of drug target prediction, and discloses a drug target intelligent prediction method and system, and the method comprises the following steps: 1, obtaining the structure data and sequence data of a target protein, and the homologous sequence data of the target protein; 2, performing molecular dynamics simulation according to the structural data, and calculating to obtain a dynamic conformation feature vector; according to the sequence data, an evolutionary information feature vector is obtained through calculation; analyzing the structural data to obtain an interaction feature vector; 3, obtaining an enhanced dynamic conformation feature vector, an enhanced evolutionary information feature vector and an enhanced interaction feature vector through an attention fusion mechanism, respectively obtaining importance weights through a gating fusion mechanism, and obtaining a fusion feature vector by adopting element-by-element multiplication and combining the importance weights; and 4, inputting the fusion feature vector into a graph neural network prediction model to obtain a target druggability probability.

Disclosed are a new interleukin-2 (IL-2) mutant protein and the use thereof. Compared with wild-type IL-2, the IL-2 mutant protein has improved properties, such as an improved IL-2 receptor binding property and improved druggability. Also provided are a fusion protein, dimer and immunoconjugate comprising the IL-2 mutant protein, nucleic acids encoding the IL-2 mutant protein, the dimer and the immunoconjugate, and a vector and host cell comprising the nucleic acid. Further provided are methods for preparing the IL-2 mutant protein, the fusion protein, the dimer and the immunoconjugate, a pharmaceutical composition containing same, and the therapeutic use thereof.

A Claudin18.2 humanized antibody and application thereof. The antibody contains a chain variable region (CDR) sequence selected from at least one of the following or an amino acid sequence having at least 90% identity therewith: light chain CDR sequences: SEQ ID NOs: 1-3 and 7-9; and heavy chain CDR sequences: SEQ ID NOs: 4-6 and 10-12; The antibody or an antigen-binding fragment thereof have humanized modification. The humanized antibody can specifically target and bind Claudin18.2, has the same in vitro activity as a human-mouse chimeric anti-Claudin18.2 monoclonal antibody, meets the requirements of druggability, and has significantly prolonged in vivo half-life.

This invention relates to the field of chelating drug research, specifically to chelating ligand compounds, targeted chelating ligands and their complexes and applications. Compared with the prior art, the targeted molecule linking sites and linking methods disclosed in this invention have better targeting and in vivo stability. At the same time, the design of the targeted molecule linking sites in this invention can improve in vivo metabolism and distribution, thereby improving the druggability of preferred compounds and providing a better foundation for the clinical application of therapeutic radiopharmaceuticals.

The invention discloses an anti-DLL3 antibody as well as a preparation method, a drug conjugate and application thereof. The anti-DLL3 antibody disclosed by the invention has very good internalization activity, relatively good binding activity with human DLL3 protein and relatively strong affinity at the protein level; the DLL3-targeting antibody coupling drug has good druggability, biological activity and in-vivo and in-vitro anti-tumor activity, and application of cytotoxic drugs in treatment of tumor patients with neuroendocrine characteristics including SCLC can be realized by the DLL3-targeting antibody coupling drug.

The invention belongs to the technical field of recombinant adeno-associated virus production, and discloses an rAAV production method and application. The invention provides an rAAV production method. The rAAV production method comprises the following steps: adding a cell death regulation inhibitor into a cell culture solution during rAAV production; the cell death regulation and control inhibitor is a cell apoptosis (Apoptosis) inhibitor and / or a necroptosis (Necroptosis) inhibitor. The production efficiency of the rAAV and the quality and purity of the rAAV product can be remarkably improved, the purpose of improving the quality of the rAAV product is achieved, the safety and druggability of rAAV related gene therapy products are further improved, and low-cost and large-scale production of the rAAV can be effectively promoted.

Provided in the present invention are a compound for the targeted degradation of BTK and the anti-tumor use thereof. In particular, in the present invention, a series of compounds are prepared and screened, the inhibitory and degradation activities of said compounds against Bruton's tyrosine kinase (BTK) are verified, and finally a compound with good druggability is found. The compound can be used for treating diseases associated with the activity or the expression quantity of Bruton's tyrosine kinase (BTK).

The invention relates to application of peroxidase reductase 1 as a target spot in preparation of an IS treatment medicine, and belongs to the technical field of biological medicine. The method comprises the steps of high-sensitivity blood immune proteome map construction, large-scale independent queue longitudinal correlation verification, cross-racial and multi-tissue causal correlation verification, targeted experiment verification and mechanism exploration, target druggability evaluation, treatment potential confirmation and the like, and selects immune response proteins with significant differences between patients and controls. The immune response protein strongly related to the onset risk of the cerebral arterial thrombosis (IS) is further screened from plasma, cerebrospinal fluid and brain tissue samples, and finally the cerebral arterial thrombosis traditional Chinese medicine target peroxide reductase 1 (PRDX1) is found. A drug, such as a PRDX1 agonist or overexpression PRDX1, designed aiming at the drug target can effectively improve the progress of the IS disease.

The invention relates to a thermal-stable KGF-2 derivative for increasing molecular internal interaction based on artificial intelligence, and a generation method, device and application of the thermal-stable KGF-2 derivative. The thermal stability type KGF-2 derivative is obtained by mutating a lysine residue at the 103th site of wild type KGF-2 into an aspartic acid residue, mutating a cysteine residue at the 106th site of the wild type KGF-2 into an aspartic acid residue and removing amino acid residues at the 2nd to 68th sites; the amino acid sequence of the heat-stable KGF-2 derivative is as shown in SEQ ID NO: 4. According to the scheme provided by the invention, the molecular structure of the KGF-2 protein can be improved by utilizing artificial intelligence rational design, a hydrogen bond network in the KGF-2 protein molecule is increased, and interaction among atom nodes is enhanced, so that the stability and druggability of the KGF-2 protein are effectively improved.

Disclosed are an anti-CDCP1 antibody or an antigen-binding fragment thereof, a nucleic acid molecule encoding same and a method for preparing same. The anti-CDCP1 antibody or the antigen-binding fragment thereof has a target-binding capacity, a tumor cell-binding capacity, an endocytosis capacity, a capability to inhibit the migration of tumor cells, and druggability. Further disclosed is a conjugate of the antibody or the antigen-binding fragment thereof. Also disclosed are a pharmaceutical composition comprising the antibody or the antigen-binding fragment thereof, and use thereof in preparing a medicament for preventing and / or treating a disease related to CDCP1, such as a tumor.

The present invention is based on the discovery of a proteolysis targeting compound having tissue targeting capability and use thereof, relating to medicinal products, and to such a compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, or a polymorph. The compound is a proteolysis targeting chimera (PROTAC) with specific tissue targeting ability. The compound structure comprises three parts, i.e., A-BD-CON, wherein the part A is a PROTAC, one end of the structure thereof is a target protein ‘binding ligand, and the other end is a ubiquitin ligase ligand; and the part CON is a ligand of an asialoglycoprotein receptor (ASGPR), enabling the specific tissue targeting function. The compound enriches in liver tissue and is able to target cells in the tissue. The invention achieves improved druggability of the PROTAC with higher solubility and cellular membrane permeability, therefore produces enhanced pharmaceutical effect on the specific target tissue.

The invention provides a virtual screening method for high-importance compounds of traditional Chinese medicine compounds, and belongs to the technical field of pharmacology. The virtual screening method comprises the following steps: S1, identifying compound components through mass spectrometry, and screening high-credibility compounds based on a monarch, minister, assistant and guide principle in combination with a UNIQ system; s2, performing KEGG enrichment analysis and disease modular network comparison to obtain a potential regulation compound; s3, evaluating high-drug-likeness compounds with high drug-likeness screening scores by adopting a QED scoring system; and S4, performing GO-BP / KEGG enrichment analysis through CHM-FIEFP software, and calculating high-importance compounds with high fitting scores by using an entropy weight method. According to the method, not only are mass spectrum detection feasibility analysis and a multi-database verification system integrated, but also the targeting and correlation of compound screening in the traditional Chinese medicine compound are remarkably improved by introducing disease-specific multi-omics data analysis.

The invention relates to a virus NSP12 protein degradation agent as well as a preparation method and application thereof. Specifically, the invention relates to a compound with a structure as shown in A-L-B (formula I) or a stereoisomer or pharmaceutically acceptable salt thereof. The compound disclosed by the invention can effectively degrade coronavirus NSP12 protein and inhibit coronavirus infection, and has good druggability.

The present application provides a compound or a pharmaceutically acceptable salt, ester, or solvate thereof. The compound provided in the present application has a structure represented by the following formula (I), wherein ring A is a benzene ring or a 5- or 6-membered heteroaromatic ring. Compared with a dual-motif CAIX inhibitor XYIMSR, the compound of formula (I) or the pharmaceutically acceptable salt, ester, or solvate thereof provided in the present application has relatively strong affinity for CAIX and a relatively small molecular volume. On the basis of the small-molecule structure, when the compound is used as a carrier for a radiopharmaceutical, the obtained small-molecule radiopharmaceutical has excellent pharmacokinetic properties and druggability, thereby providing a solution for clinical application.

The invention relates to the technical field of biological medicine, and particularly discloses a screening method and application of a 1H-pyrazolo [3, 4-b] pyridine derivative as an HDAC8 inhibitor. According to the method, firstly, based on artificial intelligence and molecular simulation technologies, druggability screening and PAINS property filtering, a sequence-based compound-protein interaction prediction model, a ligand-receptor binding affinity prediction model, cascade molecular docking, molecular dynamics simulation and other strategies are comprehensively applied; an efficient HDAC8 targeted drug screening pipeline is constructed; and an enzymatic experiment and anti-tumor cell proliferation activity evaluation are further combined, so that the selective HDAC8 small-molecule inhibitor with the 1H-pyrazolo [3, 4-b] pyridine skeleton is successfully obtained finally. The small molecule not only has strong HDAC8 inhibitory activity, but also has the potential of treating leukemia and colorectal cancer, and has a very wide application prospect.

The present application relates to the technical field of drug target prediction, and discloses a drug target intelligent prediction method and system, the drug target intelligent prediction method comprising the following steps: step 1: obtaining structural data and sequence data of a target protein and homologous sequence data of the target protein; step 2: performing molecular dynamics simulation according to the structural data to calculate a dynamic conformation feature vector; calculating an evolutionary information feature vector according to the sequence data; obtaining an interaction feature vector by analyzing the structural data; step 3: obtaining an enhanced dynamic conformation feature vector, an enhanced evolutionary information feature vector and an enhanced interaction feature vector through an attention fusion mechanism, and then obtaining importance weights respectively through a gating fusion mechanism, and obtaining a fusion feature vector by element-by-element multiplication combined with the importance weights; step 4: inputting the fusion feature vector into a graph neural network prediction model to obtain a target druggability probability.

The invention discloses a traditional Chinese medicine prescription effective small molecule identification method fusing EGA and PPO algorithms, and relates to the technical field of traditional Chinese medicine decoction small molecule identification, and the method comprises the following steps: constructing a molecular seed bank containing TPACD known components and phytochemicals with similar structures, simulating material selection, conversion and recombination mechanisms in a traditional Chinese medicine decoction process through EGA, and identifying the effective small molecules in the traditional Chinese medicine decoction process. Three parallel modules of a basic multi-objective genetic algorithm (BMGA), an enhanced multi-objective genetic algorithm (EMGA) and an intelligent multi-objective genetic algorithm (IMGA) are established by combining sequential decision optimization capability of PPO reinforcement learning, and anti-CRC lead molecules with effectiveness, stability and druggability are screened out through molecular evolution, targeted screening, iterative refining and closed-loop feedback. The molecules generated by the invention are obviously superior to the original component of TPACD in drug-likeness, structural stability and anti-CRC activity, the IMGA module has the best comprehensive performance, and an efficient and explainable new strategy is provided for excavation of active components of traditional Chinese medicine compounds.

The invention belongs to the technical field of recombinant adeno-associated virus production, and discloses an rAAV plasmid system of a high-yield cytotoxic gene and an application of the rAAV plasmid system. The rAAV plasmid system of the high-yield cytotoxic gene comprises a transgenic plasmid, a packaging plasmid and an auxiliary plasmid, the helper plasmid comprises a gene sequence of an apoptosis inhibition factor xIAP. According to the present invention, the target auxiliary gene can be highly expressed during the production of the rAAV containing the cytotoxic gene, such that the production efficiency of the rAAV is effectively improved, and the technical effects of improving the druggability of the rAAV and reducing the production cost are achieved.

The invention belongs to the technical field of polypeptide library construction, and particularly relates to a method for constructing a thiazole polypeptide library based on a phage display technology. The method comprises the following steps: firstly, introducing a thiazole group on a polypeptide chain by using thiazole synthetase, and determining the sequence preference of the enzyme through a model peptide so as to guide library design; and integrating a gene for coding the enzyme into a host bacterium genome by utilizing CRISPR-Cas9, and constructing a stably expressed chassis cell. Carrying out PCR (Polymerase Chain Reaction) amplification on a phage vector, carrying out NotI enzyme digestion and T4 connection to construct a DNA (Deoxyribose Nucleic Acid) library, and electrically transforming the DNA library to a chassis cell to obtain a phage library for displaying the thiazole modified polypeptide. The phage display of the skeleton modified polypeptide is realized for the first time, the structural diversity of the phage display polypeptide is obviously expanded by introducing the thiazole group with unique physicochemical properties, the polypeptide stability and membrane permeability are improved, and a new technical platform is provided for screening of high-affinity polypeptide and development of druggability lead compounds.

The present invention belongs to the field of biomedicine. Provided are a bispecific antibody and the use thereof. The bispecific antibody contains a first antigen-binding domain targeting PD-L1 and a second antigen-binding domain targeting 4-1BB. The antibody retains the activity of an anti-PD-L1 antibody, achieves a balance between activity and safety, and has an excellent druggability potential.

The present application relates to the technical field of nucleic acids, and discloses an siRNA for inhibiting URAT1 gene expression, and a modification and use thereof. Specifically, the present application provides a double-stranded RNA molecule targeting a URAT1 gene, and a modification thereof. Both in vivo and in vitro experiments demonstrate that the double-stranded RNA molecule and the modification thereof provided in the present application can effectively inhibit URAT1 gene expression. It is demonstrated that the double-stranded RNA molecule and the modification thereof provided in the present application have great druggability and application value in the prevention and / or treatment of diseases associated with abnormal URAT1 gene expression, such as hyperuricemia-related gout, hypertension, atherosclerosis, insulin resistance, and diabetes.

This invention belongs to the field of biotechnology and discloses a high-yield rAAV plasmid system and its applications. The high-yield rAAV plasmid system of this invention includes a transgenic plasmid containing two terminal inverted repeat sequences, a packaging plasmid, a helper plasmid, and an shRNA expression cassette; the shRNA expression cassette includes a sequence capable of targeting the target gene in the transgenic plasmid. In the rAAV production process, the plasmid system of this invention inhibits the transcriptional expression of the target gene by expressing shRNA to target the coding region or target sequence of the target gene on the transgenic plasmid. The carefully designed target sequence, unlike coding regions of human and mammalian genes, can be broadly used in various transgenic plasmids, thereby increasing rAAV yield and significantly improving the rAAV production efficiency of mammalian cells, achieving the technical effects of improved rAAV druggability and reduced production costs.

Disclosed in the present invention are a Sulfoximine linker-containing degradation agent, an intermediate thereof and a use thereof. The Sulfoximine linker-containing degradation agent of the present invention is a compound as represented by formula I or a pharmaceutically acceptable salt thereof. The degradation agent of the present invention exhibits strong target protein degradation activity, favorable pharmacological efficacy, and good prospect for druggability.

The invention relates to the field of drug development, and discloses a molecular druggability potential scoring method based on a comparative learning variational auto-encoder, which comprises the following steps: constructing a sample set comprising drug molecules and non-drug molecules, preprocessing the sample set and predicting to obtain ADMET characteristic spectrums, evaluating and sequencing the importance of the ADMET characteristic spectrums, and determining the druggability potential of the drug molecules according to the druggability potential of the drug molecules and the non-drug molecules. Screening out a druggability related characteristic set; a UniMol-based multi-task learning model is adopted to predict ADMET properties, an RDKit chemoinformatics tool is adopted to calculate physicochemical properties and synthesis feasibility scores, and a one-dimensional molecular feature vector is formed through fusion; taking the one-dimensional molecular feature vector as the input of a variational auto-encoder model adopting a fused triple contrast learning mechanism for training, and constructing a potential space; and mapping the approved drug molecules and the to-be-evaluated molecules into a potential space, and calculating druggability scores based on the Euclidean distance between the to-be-evaluated molecules and the distribution center and the local drug molecule density. The method is suitable for druggability comprehensive evaluation of drug screening, pilot optimization and molecular design.

The present disclosure belongs to the technical field of medicinal chemistry, and relates to novel crystal forms of xanomeline pamoate or deuterated xanomeline pamoate, a preparation method therefor, and the use thereof in the field of medicine. The present disclosure particularly relates to two novel crystal forms B3 and E of xanomeline pamoate represented by formula I and a novel crystal form d-B3 of deuterated xanomeline pamoate represented by formula II. The crystal form B3 exhibits good physical and chemical stabilities, can maintain an effective concentration for long time in vivo while maintaining the crystal form unchanged, has obviously relieved medicinal toxicity and side effects and possesses good druggability. Applying the crystal forms of the present disclosure by various routes of administration (e.g. intramuscular injection, subcutaneous injection, oral administration, etc.) can all achieve an expected sustained-release effect. Furthermore, the crystal forms of the present disclosure involve a simple preparation process and have a small inter-batch difference and thus are suitable for industrial production.

The invention belongs to the technical field of polypeptide preparation and biological medicine, and particularly relates to a pilose antler polypeptide, a virtual enzymolysis preparation method thereof and application of the pilose antler polypeptide in the anti-aging aspect. The eight pilose antler polypeptides provided by the invention are polypeptides which are screened from pilose antler proteins and have DRP1 inhibitory activity, and have relatively high anti-aging activity and clear action mechanism; through prediction, it is found that the compound is free of toxicity and sensitization, high in DRP1 target combining capacity, good in druggability and application safety and capable of being used for developing anti-aging products, and a new lead compound is provided for research and development of new drugs, health care products or cosmetics. Furthermore, the pilose antler polypeptide is obtained based on a virtual enzymolysis preparation method, a set of complete and efficient pilose antler anti-aging peptide computer screening process is established, virtual enzymolysis, activity prediction, safety evaluation and targeted molecular docking are organically combined, the blindness of a traditional separation technology is overcome, and the separation efficiency is improved. The screening efficiency and the success rate are obviously improved.