142 results about "Binding pocket" patented technology

The invention provides polypeptides comprising a variant heavy chain variable framework domain (VFR). In some embodiments, the amino acids defining the VFR form a loop of an antigen binding pocket. In an embodiment, the polypeptide is a variable domain of a monobody and has a variant VFR. The polypeptide may optionally comprise one or more complementary determining regions (CDRs) of antibody variable domains. In an embodiment, the polypeptide is a variable domain of a monobody and has a variant VFR and one or more variant CDRs. Libraries of polypeptides that include a plurality of different antibody variable domains generated by creating diversity in a VFR, and optionally, one or more CDRs are provided and may be used as a source for identifying novel antigen binding polypeptides that can be used therapeutically or as reagents. The invention also provides fusion polypeptides, compositions, and methods for generating and using the polypeptides and libraries.

The invention provides polypeptides comprising a variant heavy chain variable framework domain (VFR). In some embodiments, the amino acids defining the VFR form a loop of an antigen binding pocket. In an embodiment, the polypeptide is a variable domain of a monobody and has a variant VFR. The polypeptide may optionally comprise one or more complementary determining regions (CDRs) of antibody variable domains. In an embodiment, the polypeptide is a variable domain of a monobody and has a variant VFR and one or more variant CDRs. Libraries of polypeptides that include a plurality of different antibody variable domains generated by creating diversity in a VFR, and optionally, one or more CDRs are provided and may be used as a source for identifying novel antigen binding polypeptides that can be used therapeutically or as reagents. The invention also provides fusion polypeptides, compositions, and methods for generating and using the polypeptides and libraries.

The present invention provides crystalline molecules or molecular complexes which comprise binding pockets of Aurora-2 or its homologues. The invention also provides crystals comprising Aurora-2. The present invention also relates to a computer comprising a data storage medium encoded with the structural coordinates of Aurora-2 binding pockets and methods of using a computer to evaluate the ability of a compound to bind to the molecule or molecular complex. This invention also provides methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention provides methods of using the structure coordinates to screen for and design compounds, including inhibitory compounds, that bind to Aurora-2 or homologues thereof.

A fragment-based strategy, involving “multicomponent reaction chemistry” (MCR), can identify novel chemotypes that disrupt the p53 / MDM2 or p53 / MDM4 complex employs. This approach uses high resolution structural information to delineate the region of a first protein or a ligand that is nestled within the binding pocket of a second target protein. The identified region is imported into a database containing MCR scaffolds to generate a virtual library of compounds, which subsequently are docked into the binding pocket of the target protein. Results from docking then are used to select compounds for synthesis and screening. A complementary, NMR-based methodology allows for screening the ability of compounds, selected using MCR, to disrupt the p53 / MDM2 or p53 / MDM4 complex.

The invention discloses a solid elastic ball, which comprises a built-in foamed polyurethane ball center and a spherical latex bag wrapped on the outer wall of the polyurethane ball center. The outer wall of the latex bag is sprayed with polyurethane varnish and polyurethane wear-resistant oil. The invention also discloses a method for manufacturing the solid elastic ball, which includes the following steps: a. inject polyurethane material into the spherical hollow latex bag; b. put the latex bag filled with solid polyurethane material into the mould, and foam and shape it; c. 1. Trim and level the feed port of the latex bag, and spray polyurethane varnish and wear-resistant oil on the spherical surface of the latex bag to finish the finished product. Compared with the prior art, the present invention has the advantages of: the combination degree of the center of the ball and the latex bag of the wrapping layer outside the center of the ball is greatly improved, the latex bag is evenly stressed, the sphere is not easy to deform, the outer wall of the latex bag has good integrity, and there is no foaming. Phenomena such as delamination and rough handle do not exist at all, which also improves the brightness and wear resistance of the ball, and facilitates the subsequent surface spraying process.

Structural differences in binding pockets of members of the HSP90 family can be exploited to achieve differential degradation of kinases and other signaling proteins through the use of designed small molecules which interact with the N-terminal binding pocket with an affinity which is greater than ADP and different from the ansamycin antibiotics for at least one species of the HSP90 family. Moreover, these small molecules can be designed to be soluble in aqueous media, thus providing a further advantage over the use of ansamycin antibiotics. Pharmaceutical compositions can be formulated containing a pharmaceutically acceptable carrier and a molecule that includes a binding moiety which binds to the N-terminal pocket of at least one member of the HSP90 family of proteins. Such binding moieties were found to have antiproliferative activity against tumor cells which are dependent on proteins requiring chaperones of the HSP90 family for their function. Different chemical species have different activity, however, allowing the selection of, for example Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess an inherent targeting capacity. In addition, the small molecules can be linked to targeting moieties to provide targeting of the activity to specific classes of cells. Thus, the invention further provides a method for treatment of diseases, including cancers, by administration of these compositions. Dimeric forms of the binding moieties may also be employed.

The invention relates to a drug target virtual screening method based on interactive fingerprints and machine learning. According to the method, based on traditional molecular docking, the interactive fingerprints of known active and non-active micromolecules and target protein are trained through machine learning to obtain a screening model of targets, and the obtained model is used for virtual screening. The specific targets are specifically trained, the specificity of each kind of targets is fully considered, and the defect of insufficient fitting of a traditional scoring function is avoided; interaction energy of each micromolecule and each residue in a binding pocket is calculated, so that effective binding sites or binding modes can be found; non-linear fitting is carried out through machine learning, and compared with linear fitting, the correlation or coupling effect between all the interaction energy can be better processed; by means of the method, enrichment of active molecules is better promoted.

A solved three-dimensional crystal structure of a glucocorticord receptor (GR) α ligand binding domain polypeptide is disclosed, in the form of a crystalline glucocorticord receptor α ligand binding domain polypeptide in complex with the ligand fluticasone propionate (FP) and a peptide derived from the co-activator TIF2. The GR / FP / TIF2 structure includes an expanded binding pocket not seen in other GR structures. Methods of designing steroid and non-steroid modulators of the biological activity of GR and other nuclear receptors (NRs) are also disclosed. In another aspect of the present invention homology models of androgen receptor (AR), progesterone receptor (PR) and mineralcorticoid receptor (MR) are disclosed, as well as methods of forming homology models for other NRs. Methods of forming a soluble GR / FP / TIF2 complex are also disclosed.

The present invention relates to small molecule antagonists of Bcl-2 family proteins such as Bcl-2 and / or Bcl-XL. In particular, the present invention provides non-peptide cell permeable small molecules (e.g., tricyclo-dibenzo-diazocine-dioxides) that bind to a pocket in Bcl-2 / Bcl-XL that block the anti-apoptotic function of these proteins in cancer cells and tumor tissues exhibiting Bcl-2 protein overexpression. In preferred embodiments, the small molecules of the present invention are active at the BH3 binding pocket of Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Mcl-1). The compositions and methods of the present invention are useful therapeutics for cancerous diseases either alone or in combination with chemotherapeutic or other drugs.

The invention relates to the X-ray crystal structure of the hepatitis C virus helicase domain. More specifically, the invention relates to crystallized complexes of HCV helicase and an oligonucleotide, to crystallizable compositions of HCV helicase and an oligonucleotide and to methods of crystallizing an HCV helicase-oligonucleotide complex. The invention further relates to a computer programmed with the structure coordinates of the HCV helicase oligonucleotide binding pocket or the HCV helicase nucleotide triphosphate pocket wherein said computer is capable of displaying a three-dimensional representation of that binding pocket.

The present invention relates to inhibitors of GSK-3 and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors and methods of utilizing those compositions in the treatment and prevention of various disorders, such as diabetes and Alzheimer's disease. In addition, the invention relates to molecules or molecular complexes which comprise binding pockets of GSK-3β or its homologues. The invention relates to a computer comprising a data storage medium encoded with the structure coordinates of such binding pockets. The invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. The invention relates to methods of using the structure coordinates to screen for and design compounds that bind to GSK-3β protein or homologues thereof. The invention also relates to crystallizable compositions and crystals comprising GSK-3β protein or GSK-3β protein complexes.

The HCV NS5B polymerase, when complexed with certain inhibitors, adopts a conformation in which the finger loop region defined by amino acid residues 18 to 35 is displaced to expose a binding pocket defined generally by amino acid residues 392, 393, 395, 396, 399, 424, 425, 428, 429, 492, 493, 494, 495, 496, 500 and 503. This newly exposed binding pocket defines a novel target in the search of further chemical entities which are capable of binding to HCV NS5B and modulating, or preferably inhibiting, the polymerase activity of HCV NS5B.

The invention discloses a method for predicting the binding free energy of protein and ligand based on a progressive neural network, and belongs to the technical field of computer-aided drug design. The method comprises the steps: obtaining a pdb file from a PDBbind database, establishing local database, acquiring an amino acid molecule within 4.5 angstroms in the protein binding pocket by takingthe ligand molecule as a center, performing extended connectivity fingerprint calculation, carrying out SPLIF fingerprint calculation, searching for the number of salt bridges and hydrogen bonds between protein and ligand molecules, converting the structural information of the protein and the ligand into a one-dimensional tensor, and establishing a training set, a verification set and a test set;training the progressive neural network by using the training set; optimizing and searching hyper-parameters for prediction; through comparison with a molecular docking result, obtaining a higher Pearson correlation coefficient. According to the invention, the technical problem of how to convert a three-dimensional structure of protein and ligand molecules into tensors which are easy to calculateby a computer and input the tensors into the progressive neural network for training and optimization is solved, and the calculation rate and the prediction accuracy are greatly improved.

The present invention provides methods and compositions for treating autoimmune diseases and other unwanted immune reactions comprising administering a copolymer that binds to one or more HLA-DQ molecules and modulates DQ-restricted T cell responses. The copolymers are random copolymers of amino acids and copolymers comprising anchor residues to facilitate binding to the DQ binding pockets.

The present invention provides crystalline molecules and molecular complexes that comprise binding pockets of Sykcat and its homologues. The invention also provides crystals comprising the catalytic domain of Syk protein. The invention further provides a computer comprising a data storage medium encoded with the structure coordinates of Sykcat binding pockets and methods for using a computer to evaluate the ability of a chemical entity or compounds to bind to a crystalline molecule or molecular complex of the invention. This invention also provides methods of using the structure coordinates to solve the structure homologous proteins or protein complexes. The invention further provides methods of using the structure coordinates to screen for, design and optimize chemical entities or compounds, including inhibitory compounds, that bind to the catalytic domain of Syk or homologues thereof.

An inhibitor-resistant HCV NS3 protease is provided which is useful to screen for compounds having therapeutic value against drug resistant HCV strains. In particular, the inhibitor-resistant HCV NS3 protease comprises an amino acid sequence which is mutated in the substrate binding pocket thereof rendering the protease resistant to inhibitor. In a specific aspect of the present invention, at least one of the amino acids at position 155, 156 and 168 of the HCV NS3 protease is mutated to yield an inhibitor-resistant protease.

The present invention relates to small molecule antagonists of Bcl-2 family proteins such as Bcl-2 and / or Bcl-XL. In particular, the present invention provides non-peptide cell permeable small molecules (e.g., tricyclo-dibenzo-diazocine-dioxides) that bind to a pocket in Bcl-2 / Bcl-XL that block the anti-apoptotic function of these proteins in cancer cells and tumor tissues exhibiting Bcl-2 protein overexpression. In preferred embodiments, the small molecules of the present invention are active at the BH3 binding pocket of Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Mcl-1). The compositions and methods of the present invention are useful therapeutics for cancerous diseases either alone or in combination with chemotherapeutic or other drugs.

In one aspect, the disclosure provides neutralizing antibodies against JCV and methods for the treatment of PML. In some embodiments, aspects of the invention relate to an isolated JC-virus neutralizing monoclonal antibody against JCV capsid protein VPI (JCV-VP1). In some embodiments, the antibody suppresses infectivity of the JC-virus. In some embodiments, the antibody binds the sialic acid binding pocket of JCV-VPI. In some embodiments, the antibody binds JCV-VP 1 comprising one or more of the following mutations: S269F, S269Y, S267F, N265D, Q271 H, D66H, K60E, K60N and L55F.

The present invention provides crystalline molecules or molecular complexes which comprise binding pockets of Aurora-2 or its homologues. The invention also provides crystals comprising Aurora-2. The present invention also relates to a computer comprising a data storage medium encoded with the structural coordinates of Aurora-2 binding pockets and methods of using a computer to evaluate the ability of a compound to bind to the molecule or molecular complex. This invention also provides methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention provides methods of using the structure coordinates to screen for and design compounds, including inhibitory compounds, that bind to Aurora-2 or homologues thereof.

The total synthesis and evaluation of key analogs of vancomycin containing single atom changes in the binding pocket are disclosed as well as their peripherally modified, N-(hydrophobe-substituted) derivatives exemplified by a N-4-(4′-chlorob-phenyl)-methyl derivative and their pharmaceutically acceptable salts are disclosed. Their evaluation indicates the combined pocket and peripherally modified analogs exhibit a remarkable spectrum of antimicrobial activity and truly impressive potencies against both vancomycin-sensitive and -resistant bacteria, and likely benefit from two independent and synergistic mechanisms of action. A pharmaceutical composition containing a contemplated compound or its pharmaceutically acceptable salt is disclosed, as is a method of treating a bacterial infection in a mammal by administering an antibacterial amount of a contemplated compound or its salt as above to an infected mammal in need of treatment.

Crystalline IGF-1 is provided along with a method for production thereof. Crystallizing IGF-1 comprises the steps of mixing an aqueous solution comprising IGF-1 with a reservoir solution comprising a precipitant to form a mixture; and crystallizing the mixture, optionally also recrystallizing and isolating the crystalline IGF-1. In addition, a method for identifying IGF-1 indirect agonists is provided using a detergent as a standard for the level of inhibition of binding of IGFBP-1 or IGFBP-3 to IGF-1 and / or using the coordinates of the binding pockets of IGF-1 to which a candidate indirect agonist binds for structure-based drug design.

The present invention relates to glutamate dehydrogenase mutants and their application in preparation of L-phosphinothricin. The amino acid sequences of the glutamate dehydrogenase mutants are as shown in SEQ ID NO. 1˜9, 11, 13, 15, 17˜19 and 22. By means of molecular engineering, mutating the specific alanine in glutamate dehydrogenase substrate-binding pocket into glycine and / or mutating the specific valine in glutamate dehydrogenase substrate-binding pocket into alanine, the present invention has obtained NADPH-specific glutamate dehydrogenase mutants with high enzyme activity in catalyzing the substrate 2-oxo-4-[(hydroxy)(methyl)phosphinoyl]butyric acid or its salt for L-phosphinothricin preparation or NADH-specific glutamate dehydrogenase mutants with catalytic activity toward PPO; this has significantly improved substrate conversion, and increased the product concentration of the L-phosphinothricin preparation process.

The invention relates to a method for extracting a protein-micromolecule interaction module. The method specifically comprises: firstly, performing quantitative description on atoms (or amino acids) forming a micromolecular binding pocket on protein according to properties of the atoms (or amino acids); secondly, estimating the distance between the every two pocket atoms (or amino acids), and establishing a distance matrix; thirdly, extracting categories of the pocket atoms (or amino acids) with similar properties by utilizing a clustering algorithm; and finally, performing post-processing to obtain the protein-micromolecule interaction module. The method can be applied to multiple aspects of bioinformatics research, protein design, drug screening, micromolecular chemical synthesis and the like.

The invention relates to crystalline molecules or molecular complexes that comprise binding pockets of mitogen activated protein kinase activated protein kinase 2 (MAPKAPK2) or its homologues. The invention also relates to crystals comprising MAPKAPK2. The present invention also relates to a computer comprising a data storage medium encoded with the structural coordinates of MAPKAPK2 binding pockets and methods of using a computer to evaluate the ability of a compound to bind to the molecule or molecular complex. This invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention relates to methods of using the structure coordinates to screen for, design and optimize compounds, including agonists and antagonists, which bind to MAPKAPK2 or homologues thereof.

Crystalline IGF-1 is provided along with a method for production thereof. Crystallizing IGF-1 comprises the steps of mixing an aqueous solution comprising IGF-1 with a reservoir solution comprising a precipitant to form a mixture; and crystallizing the mixture, optionally also recrystallizing and isolating the crystalline IGF-1. In addition, a method for identifying IGF-1 indirect agonists is provided using a detergent as a standard for the level of inhibition of binding of IGFBP-1 or IGFBP-3 to IGF-1 and / or using the coordinates of the binding pockets of IGF-1 to which a candidate indirect agonist binds for structure-based drug design.

Novel compounds that are potent inhibitors of HIV reverse transcriptase (RT) are described in the invention. Thes novel compounds also inhibit replication of a retrovirus, such as human immunodeficiency virus-1 (HIV-1). The novel compounds of the invention include analogs and derivatives of phenethylthiazolylthiourea (PETT), of dihydroalkoxybenzyloxopyrimidine (DABO), and of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). The invention additionally provides a composite HIV reverse-transcriptase (RT) nonnucleoside inhibitor (NNI) binding pocket constructed from a composite of multiple NNI-RT complexes The composite RT-NNI binding pocket provides a unique and useful tool for designing and identifying novel, potent inhibitors of reverse transcriptase.

A hydrophobic binding pocket on ubiquitin-protein ligase E3 is described, and used in designing the inhibitors disrupting ubiquitin conjugating enzyme E2 and E3 interaction. Four types of inhibitors designed by using the binding pocket are provided, which can be used for cancer treatment.

The invention relates to molecules or molecular complexes which comprise binding pockets of TAK1 or its structural homologues. The invention relates to crystallizable compositions and crystals comprising TAK1. The present invention also relates to a data storage medium encoded with the structural coordinates of molecules and molecular complexes which comprise the TAK1 or TAK1-like ATP-binding pockets. The present invention also relates to a computer comprising such data storage material. The computer may generate a three-dimensional structure or graphical three-dimensional representation of such molecules or molecular complexes. This invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention relates to methods of using the structure coordinates to screen for and design compounds, including inhibitory compounds, that bind to TAK1 or homologues thereof.