Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In eukaryotic cells, protein synthesis is regulated by a set of initiation factors (eIF) that are required for recruiting the 40 S ribosomal subunit onto the mRNA molecule. Among these proteins, eIF4GI, which is targeted by picornaviral proteases, makes a bridge between the mRNA cap structure (via eIF4E) and the 40 S ribosome (via eIF3). Recently, internal ribosome entry segment (IRES) elements have been characterized in the genomic RNA of both simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1), suggesting that viral expression of these two viruses can be regulated at the translational level. Thus, by analogy with members of the picornavirus family, we have investigated the action of the HIV-1 protease on initiation factors eIF4GI and eIF4GII using cell extracts and the rabbit reticulocyte lysate system. Our results show that eIF4GI, but not eIF4GII, is substrate for HIV-1 protease and this effect can be prevented by a HIV-1 protease inhibitor, palinavir. However, in contrast to picornaviral proteases, the cleavage of eIF4GI by HIV-1 protease occurs at multiple sites and impairs translation of both cap-dependent and IRES-containing RNAs, except for the HCV IRES, which does not require eIF4GI or eIF4GII for activity.
J Mol Biol 2002 Apr 19
PMID:In vitro cleavage of eIF4GI but not eIF4GII by HIV-1 protease and its effects on translation in the rabbit reticulocyte lysate system. 1205 64

The concept of signature as a molecular descriptor is introduced and various topological indices used in quantitative structure-activity relationships (QSARs) are expressed as functions of the new descriptor. The effectiveness of signature versus commonly used descriptors in QSAR analysis is demonstrated by correlating the activities of 121 HIV-1 protease inhibitors. Our approach to the inverse-QSAR problem consists of first finding the optimum sets of descriptor values best matching a target activity and then generating a focused library of candidate structures from the solution set of descriptor values. Both steps are facilitated by the use of signature.
J Mol Graph Model 2002 Jun
PMID:Developing a methodology for an inverse quantitative structure-activity relationship using the signature molecular descriptor. 1207 Dec 77

Because, in vivo, the HIV-1 PR ( HIV-1 protease) present a high mutation rate we performed a comparative study of the energetic behaviors of the wild type HIV-1 PR and four type of mutants: Val82/Asn; Val82/Asp; Gln7/Lys, Leu33/Ile, Leu63/Ile; Ala71/Thr, Val82/Ala. We suggest that the energetic fluctuation (electrostatic, van der Waals and torsion energy) of the mutants and the solvent accessible surface (SAS) values can be useful to explain the viral resistance process developed by HIV-1 PR. The number and localization of enzyme mutations induce important modifications of the van der Waals and torsional energy, while the electrostatic energy has an insignificant fluctuation. We showed that the viral resistance can be explored if the solvent accessible surfaces of the active site for the mutant structures are calculated. In this paper we have obtained the solvent accessible surface for a group of 15 mutants (11 mutants obtained by Protein Data Bank (PDB) file, 4 mutants modeled by CHARMM software) and for the wild type HIV-1 PR). Our study try to show that the number and localization of the mutations are factors which induce the HIV-1 PR viral resistance. The larger solvent accessible surface could be recorded for the point mutant Val 82/Phe.
J Cell Mol Med
PMID:Comparative study of some energetic and steric parameters of the wild type and mutants HIV-1 protease: a way to explain the viral resistance. 1216 10

The protease of HIV plays a critical role in the maturation of the infectious particles of the virus. The enzyme has therefore been extensively studied with the objective of developing therapeutics that inhibit viral proliferation. We have produced monoclonal antibodies specific for the HIV-1 protease, and selected those that inhibit enzyme function for use as probes to study the enzyme's activity and as an eventual aid for the development of potential inhibitors targeted to regions other than the active site. We have characterized two such mAbs, F11.2.32 and 1696, which have inhibition constants in the low nanomolar range and which recognize epitopes from different regions of the protease. The crystal structures of the two antibodies, both in the free state as well as complexes with peptide fragments corresponding to their respective epitopes, have been solved. The structural analyses, taken together with other functional data on the antibodies, suggest mechanisms of protease inhibition by these antibodies.
J Mol Recognit
PMID:Inhibition of HIV protease by monoclonal antibodies. 1244 3

In certain biologically relevant collective motions, such as protein domain motions and sub-domain motions, large amplitude movements are localized in one or a few flexible regions consisting of a small number of residues. This paper explores the possible use of normal mode analysis in probing localized vibrational torsion motions in these flexible regions that may be related to certain collective motions. The normal modes of 10 structures of five proteins in different conformation (TRP repressor, calmodulin, calbindin D(9k), HIV-1 protease and troponin C), known to have shear or hinge domain or sub-domain motion, respectively, are analyzed. Our study identifies, for each structure, unique normal modes in the 20-200 cm-1 frequency range, whose corresponding motions are primarily concentrated in the region where large amplitude torsion movements of a known domain or sub-domain motion occur. This suggests possible correlation between normal modes at 20-200 cm-1 frequency range and initial fluctuational motions leading to localized collective motions in proteins, and thus the potential application of normal mode analysis in facilitating the study of biologically important localized motions in biomolecules.
J Mol Graph Model 2003 Jan
PMID:Correlation between normal modes in the 20-200 cm-1 frequency range and localized torsion motions related to certain collective motions in proteins. 1247 29

A quantitative structure-activity relationship (QSAR) study on 48 peptidic HIV-1 protease inhibitors was performed. Fourteen a priori molecular descriptors were used to build QSAR models. Hierarchical cluster analysis (HCA), principal component analysis (PCA) and partial least squares (PLS) regression were employed. PLS models with 32/16 (model I) and 48/0 (model II) molecules in the training/external validation set were constructed. The a priori molecular descriptors were related to two energetic variables using PLS. HCA and PCA on data from model II classified the inhibitors as slightly, moderately and highly active; three principal components, the chemical nature of which has been highlighted, are enough to describe the enzyme-inhibitor binding. Model I (r(2)=0.91, q(2)=0.84) is comparable to literature models obtained by various QSAR softwares, which justified the use of a priori descriptors.
J Mol Graph Model 2003 Mar
PMID:A priori molecular descriptors in QSAR: a case of HIV-1 protease inhibitors. I. The chemometric approach. 1254 39

New directions in computational methods for the prediction of protein function are discussed. THEMATICS, a method for the location and characterization of the active sites of enzymes, is featured. THEMATICS, for Theoretical Microscopic Titration Curves, is based on well-established finite-difference Poisson-Boltzmann methods for computing the electric field function of a protein. THEMATICS requires only the structure of the subject protein and thus may be applied to proteins that bear no similarity in structure or sequence to any previously characterized protein. The unique features of catalytic sites in proteins are discussed. Discussion of the chemical basis for the predictive powers of THEMATICS is featured in this paper. Some results are given for three illustrative examples: HIV-1 protease, human apurinic/apyrimidinic endonuclease, and human adenosine kinase.
Mol Biol Rep 2002 Dec
PMID:Future directions in protein function prediction. 1254 18

The kinetic constants for the interactions between HIV-1 protease and a selection of inhibitors were determined at different pH-values using a biosensor based interaction assay. Since this technique does not involve a substrate, it was possible to determine the pH-dependencies of the association and dissociation rates of an inhibitor, without the complication of a pH-dependent enzyme-substrate/product equilibrium. The importance of these interactions was evaluated by correlating the free energy changes upon association and dissociation of inhibitors with the predicted change in electrostatic properties of the interacting groups as a result of altered pH. It was found that the kinetic parameters varied with pH in a unique manner for all inhibitors, demonstrating that the kinetic features were associated with the specific structure of each inhibitor. Association and dissociation had different pH-profiles, indicating that the two processes proceeded by different pathways/mechanisms. The energy barrier for dissociation of the enzyme-indinavir complex increased with pH from 4.1 to 7.4, while it was generally reduced for the other inhibitors as the pH was increased from 5.1 to 7.4. The pH-dependent interactions involved in the recognition/binding of inhibitors and in the stabilization of the complex were identified by analysing three-dimensional structures of enzyme-inhibitor complexes. The interaction between the pyridine nitrogen of indinavir with Arg-8 was hypothesized to be responsible for the unique pH-dependency of indinavir. The analysis revealed features of interactions that are significant for understanding enzyme function and for optimization of new drug leads. It also highlighted the importance of environmental conditions on interactions.
J Mol Recognit
PMID:Analysis of the pH-dependencies of the association and dissociation kinetics of HIV-1 protease inhibitors. 1289 70

The predicted inhibition constant (Ki) and the predicted inhibitor concentration (IC90) of the HIV-1 protease (HIV- 1 PR) inhibitors: symmetric and nonsymmetric - benzyl, ketone, oxime, pyrazole, imidazole, and triazole cyclic urea derivatives, were obtained by the 3D-CoMFA (Comparative Molecular Field Analysis) method. The CoMFA statistical parameters: cross-validate correlation coefficient (q2), higher than 0.5, and the fitted correlation coefficient (r2), higher than 0.90 validated the predicted biological activities. The best predictions were found for the trifluoromethyl ketoxime derivative (log 1/Ki predict = 8.42), the m-pyridineCH2 pyrazole derivative (log 1/Ki predict = 9.77) and the 1,2,3 triazole derivative (log 1/Ki predict = 7.03). We attempted to design a new potent HIV-1 protease inhibitor by addition of o-benzyl to the (p-HOPhCH2) pyrazole 12f derivative inhibitor. A favorable steric area surrounded the o-benzyl, suggesting a possible new potent HIV-1 protease inhibitor.
J Cell Mol Med
PMID:Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV-1 protease inhibitors. A 3D-QSAR-CoMFA method for new antiviral drug design. 1459 53

Interaction kinetic and thermodynamic analyses provide information beyond that obtained in general inhibition studies, and may contribute to the design of improved inhibitors and increased understanding of molecular interactions. Thus, a biosensor-based method was used to characterize the interactions between HIV-1 protease and seven inhibitors, revealing distinguishing kinetic and thermodynamic characteristics for the inhibitors. Lopinavir had fast association and the highest affinity of the tested compounds, and the interaction kinetics were less temperature-dependent as compared with the other inhibitors. Amprenavir, indinavir and ritonavir showed non-linear temperature dependencies of the kinetics. The free energy, enthalpy and entropy (DeltaG, DeltaH, DeltaS) were determined, and the energetics of complex association (DeltaG(on), DeltaH(on), DeltaS(on)) and dissociation (DeltaG(off), DeltaH(off), DeltaS(off)) were resolved. In general, the energetics for the studied inhibitors was in the same range, with the negative free energy change (DeltaG < 0) due primarily to increased entropy (DeltaS > 0). Thus, the driving force of the interaction was increased degrees of freedom in the system (entropy) rather than the formation of bonds between the enzyme and inhibitor (enthalpy). Although the DeltaG(on) and DeltaG(off) were in the same range for all inhibitors, the enthalpy and entropy terms contributed differently to association and dissociation, distinguishing these phases energetically. Dissociation was accompanied by positive enthalpy (DeltaH(off) > 0) and negative entropy (DeltaS(off) < 0) changes, whereas association for all inhibitors except lopinavir had positive entropy changes (DeltaS(on) > 0), demonstrating unique energetic characteristics for lopinavir. This study indicates that this type of data will be useful for the characterization of target-ligand interactions and the development of new inhibitors of HIV-1 protease.
J Mol Recognit
PMID:Kinetic and thermodynamic characterization of HIV-1 protease inhibitors. 1502 31


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