137 results about "Druggability" patented technology

The invention discloses a compound represented by a formula (1), or a tautomer, a mesomer, a raceme, an enantiomer, a diastereoisomer, or a mixture form thereof, or a pharmaceutically acceptable salt, a prodrug or a solvate thereof, the structure of the formula (1) is represented as follows: # imgabs0. Strong hydrophilic sulfonic acid inner salt and / or phosphoric acid inner salt side chains are introduced at the position of (AAA and the like)-PAB (self-destruction group), so that the druggability (including hydrophilicity and stability) of the antibody drug conjugate corresponding to the compound is greatly enhanced, the in-vivo drug removal effect is reduced, and the tumor treatment effect is improved.

A compound represented by formula (1), or a tautomer, mesomer, racemate, enantiomer, and diastereomer thereof, or mixture form thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the structure of formula (1) is as shown below: formula (1). According to the compound, a strong hydrophilic sulfonate inner salt and / or phosphate inner salt side chain are introduced at the position of polypeptide (VC, VA, AAA, etc.)-PAB (self-immolative group) of a linker, greatly enhancing the druggability (comprising hydrophilicity and stability) of an antibody drug conjugate corresponding to the compound, reducing the in-vivo drug clearance effect, and improving the tumor treatment effect.

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 relates to the field of molecular targeted therapy, and discloses an application of an SLC16A5 (MCT6) small-molecule inhibitor MCT6-Ai7-2 in preparation of a medicine for treating acute myeloid leukemia (AML). The inhibitor takes an SLC16A5 protein structure predicted by Alphafold as a target spot, and is obtained through compound database screening, molecular docking and druggability optimization. An in-vitro experiment proves that MCT6-Ai7-2 can remarkably inhibit proliferation of AML cell lines such as U937 and MOLM-13, induce cell apoptosis and retard a cell cycle, has an inhibiting effect on a primary AML patient specimen and is relatively low in toxicity to normal cells; in-vivo experiments show that the compound is effective and has good safety in AML model mice. In addition, the MCT6-Ai7-2 and the vinca can be combined to synergistically enhance the inhibition effect on vinca drug-resistant cells, and by reducing the expression of anti-apoptotic protein MCL-1, the activation of pro-apoptotic factors BIM and tBID is promoted to play a role. The invention provides a novel targeting drug and strategy for treatment of AML (especially drug-resistant or recurrent patients).

The present disclosure is a polyethylene glycol modified zwitterionic fluorescent probe. The core luminescent group of the fluorescent probe of the present disclosure is a heptamethine chain which is connected by a phenoxy bridge and has a rigid ring structure in the center. The two ends of the heptamethine chain are two sulfonic indole groups, and two polyethylene glycol chains are connected with the indole groups. A tumor targeting ligand is connected with a luminescent group through one polyethylene glycol chain and one alkaline amino acid spacer. The probe of the present disclosure can be connected with polypeptides, small molecules and antibodies having a tumor targeting function, thereby achieving near-infrared fluorescence imaging for tumor targeting. The probe of the present disclosure has good druggability, and is extremely suitable for industrial production and clinical promotion.

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 present invention enables the prediction of both the ligand type for protein-ligand binding sites and their druggability scores. The invention provides a computational method to investigate the ligand type and druggability of protein-ligand binding sites. The invention has two distinct training sets for two different prediction methods. The method leverages attention-based deep learning models for both ligand type and druggability prediction tasks. Deep learning models incorporate both channel-based and spatial-based attention mechanisms. The training phase focuses on the coordinates of known ligand binding sites to enhance the accuracy of druggability prediction. The method also provides the capability to update the training set with new data, thereby ensuring continued improvement in the prediction performance. The invention also details a computer device with a memory and processor, storing a computer program to implement the method. The device processes input in the PDB format, performs the necessary cleaning steps, and utilizes the trained models to predict ligand binding site's types and their respective druggability scores. The results are integrated into a table representation and presented to the user, offering an efficient way to understand and apply the predictions.

The provided long-acting kinin or the derivative thereof fundamentally solves the problem that kinin has no druggability, on one hand, the half-life period of kinin or the derivative thereof is prolonged through a long-acting technology, and it is prevented that kinin or the derivative thereof is rapidly degraded and inactivated in vivo; on the other hand, the action site of the kinin and the receptor is covered or partially covered through long-acting modification, so that the adverse reactions such as rapid blood pressure reduction and hypotension in a short time are effectively avoided. The long-acting kinin or the derivative thereof well retains receptor binding activity and signal transduction activity in an in-vitro cell experiment, can effectively treat hypertension and prevent or treat hypertension complications in an in-vivo experiment, and provides a new method for treating hypertension and hypertension complications.

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 discloses a podophyllotoxin triazole ether derivative as well as a preparation method and application thereof, belongs to the technical field of chemical pharmacy, and particularly relates to a podophyllotoxin triazole derivative and application of the podophyllotoxin triazole ether derivative in preparation of antitumor drugs. A series of novel 1, 2, 3-triazole podophyllotoxin derivatives are designed and synthesized by combining a triazole structure with a podophyllotoxin matrix through click chemistry reaction, the dynamic characteristics of podophyllotoxin are optimized by introducing the triazole structure, and the anti-cancer effect and druggability of podophyllotoxin are improved. Molecular docking shows that the series of compounds have relatively strong binding energy to AKT1 and tubulin and can inhibit tubulin / AKT1 in a targeted manner, and in-vitro anti-tumor activity research shows that the molecules have very strong inhibitory activity to proliferation of human colon cancer cell strains, and a new strategy can be provided for structural derivatization of podophyllotoxin. # imgabs0 #

The invention provides an antibody screening method and system based on a differential evolution algorithm and an artificial intelligence model. The method comprises the following steps: S1, acquiring data of an antibody-antigen compound sequence and affinity; s2, encoding the antibody and antigen sequences by using a language model, and converting the encoded antibody and antigen sequences into a matrix M; s3, training a machine learning model by using the matrix M and the affinity parameters to obtain a trained optimal machine learning model; s4, predicting the antigen affinity of the antibody by utilizing the trained optimal machine learning model; and S5, carrying out affinity optimization on the antibody sequence based on a differential evolution algorithm, and carrying out further filtration by predicting the druggability of the antibody so as to screen the antibody with high affinity and good drug properties.

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.

The invention belongs to the technical field of biology, and discloses a plasmid system with high rAAV yield and application. The plasmid system of the high-yield rAAV comprises a transgenic plasmid containing two terminal inverted repetitive sequences, a packaging plasmid, an auxiliary plasmid and an shRNA (short hairpin Ribonucleic Acid) expression cassette, the shRNA expression cassette comprises a sequence capable of targeting a target gene in the transgenic plasmid. According to the plasmid system, in the rAAV production process, transcription expression of a target gene is inhibited by expressing a target gene coding region or a target sequence on shRNA targeted transgenic plasmids. The well-designed target sequence is different from human and mammal source gene coding region sequences, and can be applied to various transgenic plasmids in a broad spectrum manner, so that the yield of the rAAV is increased, the rAAV production efficiency of mammal cells can be remarkably improved, and the technical effects of improving the druggability of the rAAV and reducing the production cost are achieved.

The invention relates to a nucleotide monomer compound and application thereof in nucleic acid interference (RNAi) drug molecules. After the nucleotide monomer is introduced into the siRNA antisense strand seed region, the potential off-target effect of the antisense strand seed region can be remarkably reduced, and the activity of siRNA can be maintained or improved, so that target gene mRNA is silenced with higher selectivity, the safety window of siRNA drugs is expanded, the druggability of siRNA can be improved, and the siRNA activity can be improved. Therefore, related diseases caused by the target gene mRNA can be treated more effectively. # imgabs0 #

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.

Present disclosure relates to a fusion protein, and a preparation method therefor and the use thereof. The fusion protein comprises a GSDME mutant protein and a tumor cell-specific cell-penetrating peptide. In the GSDME mutant protein, a tumor-targeting effect is provided by mutating a sequence recognized by cysteine-aspartic proteases in GSDME protein into an amino acid sequence recognized by matrix metalloproteinase; and the in-vitro misfolding rate of GSDME protein is reduced by means of mutating cysteine to alanine, increasing the druggability of the protein. The fusion protein which has a tumor targeting property, penetrating property and tumor microenvironment-specific activation is constructed, which provides a new idea for the development of targeted anti-cancer drug.

A TROP2 targeting antibody-drug conjugate, and a preparation method and use therefor. The antibody-drug conjugate is shown in formula I. Said type of compound has a good targeting property, a good inhibitory effect on tumor cells positively expressing TROP2, and good druggability and high safety. The present antibody drug conjugate has an inhibitory effect on TROP2, and also a good inhibitory effect on at least one of NCI-N87, MDA-MB-468 and BXPC3 cells.

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.

The present invention discloses an improved c-Met neutralizing antibody and a preparation method and application thereof. It belongs to the field of biopharmaceutical technology. The present invention optimizes the structure and activity of an agonistic c-Met antibody with neutralizing activity through a random mutation library of antibodies and cell display technology, obtains an antibody with high affinity and low agonistic activity, and maintains the neutralization and internalization activity of the parent antibody, thereby improving the drugability of the c-Met antibody. The obtained mutant antibody 2G5 has a good purification effect, an IC50 of 41.53ng / ml, and a strong ability to bind to the extracellular region of c-Met. The results of the blocking ELISA experiment showed that the mutant antibody 2G5 had significant neutralizing activity, and in A549 cells, the antibody caused a significant internalization effect. The mutant antibody 2G5 could not activate the c-Met signaling pathway of A549 cells, and could not cause HUVEC cell proliferation and A549 cell migration. A mutant antibody with higher drugability was obtained.

The present invention provides a lipid material for nucleic acid delivery, wherein the lipid material comprises a compound having structure I. The present invention also provides use of the lipid material for nucleic acid delivery in the preparation of a therapeutic drug for one or more selected from an infectious disease, a tumor disease, a congenital hereditary disease, and an immune disease. By means of the lipid material provided in the present invention and adopting a nucleic acid drug carrier strategy with high efficiency and low toxicity, a novel ionizable lipid and an auxiliary lipid material are mixed to encapsulate nucleic acid drugs, so that efficient and safe delivery of the nucleic acid drugs in vivo is achieved, and the druggability of the nucleic acid drugs is improved.

The invention discloses an IL-21 mutant, a fusion protein containing the IL-21 mutant, nucleic acid, a recombinant expression vector, a host cell and a preparation method and application of the IL-21 mutant. The IL-21 mutant comprises a mutant pair V28C and a mutant pair A58C compared with a wild type IL-21. The above mutation pairs can be combined with IL-21 mutation R9E / R76A, and the combination still has biological activity, so that the druggability of the finally obtained mutant is further improved.

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 relates to a nucleotide monomeric compound as shown in a formula I and application of the nucleotide monomeric compound in nucleic acid interference (RNAi) drug molecules. After the nucleotide monomeric compound is introduced to the 5'end of the siRNA antisense strand, the activity of the siRNA can be remarkably improved, and target gene mRNA can be more efficiently silenced. The druggability of the siRNA can be improved, so that related diseases caused by the target gene mRNA can be more effectively treated. # imgabs0 # can be more effectively treated.

The invention discloses a high-throughput screening method for antibacterial peptides capable of being prepared into medicines based on multi-dimensional attribute evaluation, belongs to the cross technical field of bioinformatics and innovative medicine research and development, and is suitable for an input candidate antibacterial peptide sequence set. The method comprises the following steps: carrying out antibacterial activity preliminary prediction and sorting operation on an input candidate sequence aiming at a target pathogen so as to obtain a pre-selected subset; performing multi-dimensional evaluation on the pre-selected subset based on a plurality of preset druggability indexes; in the evaluated sequence, the minimum inhibitory concentration (MIC) value of the sequence is further predicted, and finally the target antibacterial peptide is screened out according to the predicted MIC value. According to the method, through a layered and multi-module linkage screening process and application of the optimized machine learning model, the antibacterial peptide with high activity and good patent medicine potential is efficiently and accurately screened out, the screening efficiency is remarkably improved, and the research and development risk is reduced.

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.

The invention relates to a nucleotide monomeric compound as shown in a formula I and application of the nucleotide monomeric compound in nucleic acid interference (RNAi) drug molecules. After the nucleotide monomeric compound is introduced to the 5'end of the siRNA antisense strand, the activity of the siRNA can be remarkably improved, and target gene mRNA can be more efficiently silenced. The druggability of the siRNA can be improved, so that related diseases caused by the target gene mRNA can be more effectively treated. # imgabs0 # can be more effectively treated.

Disclosed are an anti-DLL3 antibody and a preparation method therefor, a drug conjugate and application thereof. The anti-DLL3 antibody in the present invention has good internalization activity, has better binding activity with human DLL3 protein, and has strong affinity at the protein level. The antibody conjugated drug targeting DLL3 in the present invention has good druggability, biological activity, and anti-tumor activity in vitro and vivo, and can achieve an application of cytotoxic drugs in treating tumor patients comprising SCLC and having neuroendocrine characteristics.

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).