Gene/Protein Disease Symptom Drug Enzyme Compound
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We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80,000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the 'red tide' dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 microM and 0.6 microM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease.
J Comput Aided Mol Des 1992 Jun
PMID:An approach to computer-aided inhibitor design: application to cathepsin L. 151 75

Receptor-based drug design is predicated on the knowledge of the structure of a target receptor and the principles of molecule recognition. The objective is to produce a wide diversity of structures that are sterically and electrostatically complementary to a specified receptor site. Many drug-receptor interactions are controlled by a few key receptor groups. This observation leads to a design approach in which one focuses on chemical fragments that putatively interact with the key receptor groups. There then remains the difficult task of joining the fragments into molecular structures that match the spatial patterns of recognition forces in the receptor site. In this paper, we describe a new modeling program, BUILDER, that combines database searching techniques and structure generation algorithms within an interactive graphics modeling environment (MidasPlus). A novel tool for process communication (delegate) is introduced and examples of its use are given. To demonstrate the functionality of the package and its ability to produce novel structures, we examine the active site of HIV-1 protease.
J Mol Graph 1992 Jun
PMID:Automated site-directed drug design using molecular lattices. 163 51

The paper is a brief account of aspartic proteinases' structural studies developed in V.A. Engelhardt Institute of Molecular Biology during the last 3 years. The work on porcine pepsin has been finalized after the refinement of the monoclinic crystal form at 1.8 A resolution performed in collaboration with the group of protein structure and function studies of the University of Alberta in Canada. An important structural property of chymosin which explains the enzyme specificity has been found. Protein engineering work on chymosin is being developed. The structural template for aspartic proteinases has been elucidated and on the basis of this template the model of HIV-1 protease molecule has been built. Some approaches to the design of HIV-1 protease inhibitors were elucidated.
Mol Biol (Mosk)
PMID:[Various aspects of structural studies of aspartate proteinases]. 269 93

In some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a specified target. The approach uses single amino acid residues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interaction sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides represent a difficulty because of their great conformational flexibility and a study of the advantages and disadvantages of this simple approach is an important step in the development of design tools. After a description of our general approach, a more detailed discussion of its adaptation to peptides is given. The method is then applied to the design of peptide-based inhibitors to HIV-1 protease and the design of structural mimics of the surface region of lysozyme. The results are encouraging and point the way towards further development of interaction site-based approaches for peptide design.
J Comput Aided Mol Des 1995 Jun
PMID:PRO_LIGAND: an approach to de novo molecular design. 4. Application to the design of peptides. 756 74

A computer procedure TFIT, which uses a molecular superposition force field to flexibly match test compounds to a 3D pharmacophore, was evaluated to find out whether it could reliably predict the bioactive conformations of flexible ligands. The program superposition force field optimizes the overlap of those atoms of the test ligand and template that are of similar chemical type, by applying an attractive force between atoms of the test ligand and template which are close together and of similar type (hydrogen bonding, charge, hydrophobicity). A procedure involving Monte Carlo torsion perturbations, followed by torsional energy minimization, is used to find conformations of the test ligand which cominimize the internal energy of the ligand and the superposition energy of ligand and template. The procedure was tested by applying it to a series of flexible ligands for which the bioactive conformation was known experimentally. The 15 molecules tested were inhibitors of thermolysin, HIV-1 protease or endothiapepsin for which X-ray structures of the bioactive conformation were available. For each enzyme, one of the molecules served as a template and the others, after being conformationally randomized, were fitted. The fitted conformation was then compared to the known binding geometry. The matching procedure was successful in predicting the bioactive conformations of many of the structures tested. Significant deviation from experimental results was found only for parts of molecules where it was readily apparent that the template did not contain sufficient information to accurately determine the bioactive conformation.
J Comput Aided Mol Des 1995 Jun
PMID:Flexible matching of test ligands to a 3D pharmacophore using a molecular superposition force field: comparison of predicted and experimental conformations of inhibitors of three enzymes. 756 76

Comparative Molecular Field Analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm (Cramer, R.D.; et al. (1988), J. Am. Chem. Soc., 110, 5959-5967), correlates variations in the (experimental) biological activity with 3D variance in the steric and electrostatic field of modeled compounds. Of general interest to the drug design area is the interpretation of CoMFA results, in order to gain maximum benefit from an established 3D-QSAR model. CoMFA studies report results using the standard deviation (stdev) times(*) coefficient (beta) field and its contributions to make SAR statements. This field is the scalar product of the absolute stdev of the CoMFA field at a lattice point and the QSAR equation coefficient (beta) at the same point. Negative beta values yield detrimental contributions, while positive beta values are considered beneficial. The QSAR equation is based on actual field values, therefore both positive and negative field values can have beneficial effect to the target property (Y), depending on the sign of beta. The results of a CoMFA model on 59 HIV-1 protease (HIV-PR) inhibitors (Waller, C.L.; et al. (1993), J. Med. Chem., 36, 4152-4160) were compared with the HIV-PR crystal structure to analyze the correspondence between CoMFA fields and ligand binding regions in the enzyme. Local steric and electrostatic interactions were analyzed in terms of various field values and beta coefficients. While redundant for some regions, other field contours besides stdev* beta bring additional information. Using this method, we observed a unique region with negative beta values for the electrostatic field (based on a -1 charged probe) located opposite of the scissile bond, between P1 and P1', where steric stdev* beta values are positive. Four hydrophobic residues in the HIV-PR crystal delimit the region, which is suggested as a new potential hydrophobic binding site for the inhibitors. The same region was confirmed using the stdev* beta contours of a HINT (Kellogg, G.; et al. (1991), J. Comput.-Aided Mol. Design, 5, 545-552) calculation on the same model. The steric, electrostatic and lipophilic fields of the CoMFA and HINT models are presented in various forms, and the information extracted is detailed.
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PMID:3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results. 757 6

We have subcloned an N-terminal extended protease gene of human immunodeficiency virus (HIV) type 1 that is encoded in the protease domain of the pol open reading frame into expression vector pGEX-KG. A relatively high level of expression of recombinant HIV-1 protease (PR) was achieved with isopropyl beta-D-thiogalactoside (IPTG) induction and glucose supplement. An isolation method consisting of denaturation of protein and followed by refolding was developed for releasing this recombinant HIV-1 PR into the soluble phase since most of the expressed protease was initially present in insoluble inclusion bodies. High purity of this recombinant HIV-1 PR was obtained by sequential purification using Sephadex G-50 gel filtration and CM-23 cellulose cation exchange chromatography, yielding the protease more than 1 mg per liter culture. N-terminal amino acid sequence analysis showed that the recombinant HIV-1 PR underwent autocleavage from the fusion protein during expression. SDS-PAGE indicated that the molecular weight of this recombinant HIV-1 PR is 11 kDa. This recombinant HIV-1 PR showed proteolytic activity for the synthetic peptide substrates corresponding to the sequence at the Gag MA/CA and Pol p6*/PR junctions. The purified enzyme whose specific activity for the heptapeptide SQNYPIV was 848.7 nmol*min-1*mg protease-1 also processed recombinant polyprotein Gag41 as its substrate.
Biochem Mol Biol Int 1995 Apr
PMID:Expression and purification of active form of HIV-1 protease from E.coli. 762 39

An approach to de novo molecular design, PRO-LIGAND, has been developed that, in the environment of a large, integrated molecular design and simulation system, provides a unified framework for the generation of novel molecules which are either similar or complementary to a specified target. The approach is based on a methodology that has proved to be effective in other studies--placing molecular fragments upon target interaction sites-but incorporates many novel features such as the use of a rapid graph-theoretical algorithm for fragment placing, a generalised driver for structure generation which offers a large variety of fragment assembly strategies to the user and the pre-screening of library fragments. After a detailed description of the relevant modules of the package, PRO-LIGAND's efficacy in aiding rational drug design is demonstrated by its ability to design mimics of methotrexate and potential inhibitors for dihydrofolate reductase and HIV-1 protease.
J Comput Aided Mol Des 1995 Feb
PMID:PRO-LIGAND: an approach to de novo molecular design. 1. Application to the design of organic molecules. 775 67

The program DOCK [1,2] has been used successfully to identify molecules which will bind to a specified receptor [3]. The original method ranks molecules based on their shape complementarity to the receptor site and relies on the chemist to bring the appropriate electrostatic or hydrogen bond properties into the molecular skeletons obtained in the search. This is useful when screening a small database of compounds, where it is not likely that molecules with both the correct shape and electrostatic properties will be found. As large databases are more likely to have redundant molecular shapes with a variety of functionality (e.g., members of a congeneric series), it would be useful to have a method which identifies molecules with both the correct shape and functionality. To this end we have modified the DOCK 1.0 method to target user-specified atom types to selected positions in the receptor site. The target sites can be chosen based on structural evidence, calculation or inspection. Targeted-DOCK improves the ability of the DOCK method to find the crystallographically determined binding mode of a ligand. Additionally, targeted-DOCK searches a database of small molecules at 100-1000 times the rate of DOCK 1.0, allowing more molecules to be screened and more sophisticated scoring schemes to be employed. Targeted-DOCK has been used successfully in the design of a novel non-peptide inhibitor of HIV-1 protease.
J Comput Aided Mol Des 1994 Jun
PMID:A shape- and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors. 796 24

Physical organic structural properties of small molecules and macromolecules such as bond count, branching and proximity between multiple polar fragments contribute significantly to measured hydrophobicity (log P). These structural properties are encoded in the Rekker and Leo methods of calculating log P as structural-dependent factors. Regardless of the size of the atom primitive set, methods predicting log P with only atom primitives can miss subtle structural detail within series of related compounds. The HINT (Hydropathic INTeractions) model for inter- and intramolecular noncovalent interactions calculates atom-based hydrophobic constants, but uses all Leo-type factors in the calculation rather than a large set of atom primitives. Two types of applications of HINT are discussed: evaluation of the binding of an inhibitor (A74704) to HIV-1 protease, where it is shown that modeling of the protonation state (i.e., Asp25, Asp125) in the protein can strongly influence perceived substrate binding; and the use of HINT to calculate a third (hydropathic) field for CoMFA can yield a statistically enhanced and predictive model for molecular design.
J Comput Aided Mol Des 1994 Feb
PMID:The effect of physical organic properties on hydrophobic fields. 803 11


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