Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel 'ureidopeptide' substrate analog inhibitor of the HIV-1 protease, created by substitution of a urea for the scissile amide bond of a hexapeptide substrate, was synthesized and tested for inhibition of HIV-1 protease. This inhibitor was designed as a stereochemical mutant of an earlier ureidopeptide inhibitor in which the P1' phenylalanine residue was changed from an l-isomer to a d-isomer. This was done in an attempt to increase binding to the enzyme by compensating for a lengthening of the peptide backbone. The inhibitor was synthesized from two protected tripeptide precursors using an oxidative Hoffmann rearrangement of a C-terminal peptide amide. The new inhibitor was found to inhibit HIV-1 protease with an observed IC(50) of 47 mum.
 ...
PMID:Exploring the stereochemical requirements for protease inhibition by ureidopeptides. 1578 65

Artificial neural networks (ANNs) were used to model both inhibition of HIV-1 protease (K(i)) and inhibition of HIV replication (IC90) for 55 cyclic urea derivatives using constitutional and 2D descriptors. As a preliminary step, linear dependences were established by multiple linear regression (MLR) approaches, selecting the relevant descriptors by genetic algorithm (GA) feature selection. For ANN models non-linear GA feature selection was also applied. Non-linear modeling of K(i) overcame the results of the linear one using four properties, keeping in mind standard Pearson R correlation coefficients (0.931 vs. 0.862) and leave one out (LOO) cross-validation analysis (Q(LOO)2 = 0.703 vs. 0.510). On the other hand, IC90 modeling was insoluble by a linear approach: no predictive model was achieved; however, a non-linear relation was encountered according to statistic results (R = 0.891; Q(LOO)2 = 0.568). The best non-linear models suggested the influence of the presence of nitrogen atoms and the molecular volume distribution in the inhibitor structures on the HIV-1 protease inhibition as well as that the inhibition of HIV replication was dependent on the occurrence of five-member rings. Finally, inhibitors were well distributed regarding its activity levels in a Kohonen self-organizing map built using the input variables of the best non-linear models.
 ...
PMID:Modeling of activity of cyclic urea HIV-1 protease inhibitors using regularized-artificial neural networks. 1620 4

As part of our efforts to identify potent HIV-1 protease inhibitors that are active against resistant viral strains, structural modification of the azacyclic urea (I) was undertaken by incorporating acyl groups as P(1)' ligands. The extensive SAR study has yielded a series of N-acyl azacyclic ureas (II), which are highly potent against both wild-type and multiple PI-resistant viral strains.
 ...
PMID:Synthesis and activity of N-acyl azacyclic urea HIV-1 protease inhibitors with high potency against multiple drug resistant viral strains. 1620 41

We present here a neural networks method designed to predict biological activity based on a local representation of the ligand. The compounds of the series are represented by a vector mapping for each of four substituent properties: volume, log P, dipole moment and a simple 'steric' parameter relating to its shape. This ligand representation was tested using neural networks on a set of 42 cyclic-urea derivatives, inhibiting HIV-1 protease. The leave-one-out cross-validation using all descriptors in the input gave a correlation factor between prediction and experiment of 0.76 for the overall set and 0.88 when three outliers were left out. To rank the significance of the four descriptors, we further tested all combinations of two and three parameters for each substituent, using two disjunctive testing sets of five inhibitors. In these sets, vectors with extreme descriptor values were used either in the training or the testing set (sets A and B, respectively). The method is a very good interpolator (set A, 95+/-2% accuracy) but a less effective extrapolator (set B, 85+/-2% accuracy). Generally, the combinations including the 'steric' parameter predict better than average, while those containing the volume are less effective. The best prediction, 98.8+/-1.2%, was obtained when log P, the dipole and the steric parameter were used on set A. At the opposite end, the lowest ranked descriptor set was obtained when replacing log P with the volume, giving 92.3+/-6.7% accuracy over the set A.
 ...
PMID:Evaluation of a neural networks QSAR method based on ligand representation using substituent descriptors. Application to HIV-1 protease inhibitors. 1632 39

We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes of the active site flaps. In particular, the unliganded protease undergoes multiple conversions between the "closed" and "semiopen" forms observed in crystal structures of inhibitor-bound and unliganded protease, respectively, including reversal of flap "handedness." Simulations in the presence of a cyclic urea inhibitor yield stable closed flaps. Furthermore, we observe several events in which the flaps of the unliganded protease open to a much greater degree than observed in crystal structures and subsequently return to the semiopen state. Our data strongly support the hypothesis that the unliganded protease predominantly populates the semiopen conformation, with closed and fully open structures being a minor component of the overall ensemble. The results also provide a model for the flap opening and closing that is considered to be essential to enzyme function.
 ...
PMID:HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations. 1641 68

We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease (HIV-PR) with a continuum solvent model that reproducibly sample closing of the active site flaps following manual placement of a cyclic urea inhibitor into the substrate binding site of the open protease. The open form was obtained from the unbound, semi-open HIV-PR crystal structure, which we recently reported (Hornak, V.; et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 915-920.) to have spontaneously opened during unrestrained dynamics. In those simulations, the transiently open flaps always returned to the semi-open form that is observed in all crystal structures of the free protease. Here, we show that manual docking of the inhibitor reproducibly induces spontaneous conversion to the closed form as seen in all inhibitor-bound HIV-PR crystal structures. These simulations reproduced not only the greater degree of flap closure, but also the striking difference in flap "handedness" between bound and free enzyme. In most of the simulations, the final structures were highly accurate. Root-mean-square deviations (RMSD) from the crystal structure of the complex were approximately 1.5 A (averaged over the last 100 ps) for the inhibitor and each flap despite initial RMSD of 2-5 A for the inhibitors and 6-11 A for the flaps. Key hydrogen bonds were formed between the flap tips and between flaps and inhibitor that match those seen in the crystal structure. The results demonstrate that all-atom simulations have the ability to significantly improve poorly docked ligand conformations and reproduce large-scale receptor conformational changes that occur upon binding.
 ...
PMID:HIV-1 protease flaps spontaneously close to the correct structure in simulations following manual placement of an inhibitor into the open state. 1650 55

Cyclic ureas form a perspective class of non-peptidic HIV-1 protease inhibitors with major bioavailability problems. Low absorption rates of DMP 323 as one of the first representatives led to investigations whether transport efflux pump P-glycoprotein (P-gp) within the intestine may be partly responsible for the low absorption rates. DMP 323 proved to be a P-gp substrate in competition studies with P-gp inhibitor ritonavir and H17 as a representative of another class of non-peptidic HIV-1 protease inhibitors. Intestinal DMP 323 absorption was mainly increased under co-application of both ritonavir and H17. DMP 323 used as a membrane efflux pump inhibitor itself showed little affinities to P-gp compared to H17 as strong P-gp inhibitor. So P-gp proved to play a decisive role in the low intestinal absorption of the cyclic urea representative DMP 323.
 ...
PMID:P-glycoprotein effects of cyclic urea HIV protease inhibitor DMP 323 in competitional absorption studies. 1704 92

Multiscale simulations (coarse-grained Brownian dynamics simulations and all-atom molecular dynamics simulations in implicit solvent) were applied to reveal the binding processes of ligands as they enter the binding site of the HIV-1 protease. The initial structures used for the molecular dynamics simulations were generated based on the Brownian dynamics trajectories, and this is the first molecular dynamics simulation of modeling the association of a ligand with the protease. We found that a protease substrate successfully binds to the protein when the flaps are fully open. Surprisingly, a smaller cyclic urea inhibitor (XK263) can reach the binding site when the flaps are not fully open. However, if the flaps are nearly closed, the inhibitor must rearrange or binding can fail because the inhibitor cannot attain proper conformations to enter the binding site. Both the peptide substrate and XK263 can also affect the protein's internal motion, which may help the flaps to open. Simulations allow us to efficiently study the ligand binding processes and may help those who study drug discovery to find optimal association pathways and to design those ligands with the best binding kinetics.
 ...
PMID:Binding pathways of ligands to HIV-1 protease: coarse-grained and atomistic simulations. 1731 52

Our ongoing efforts to understand the difference in the binding pattern of HIV-1 protease inhibitor (HIVPI) with the wild-type and mutant HIV-1 protease (HIVPR) and to provide mechanistic insight are continued further. We report here the results of a recent quantitative structure-activity relationship (QSAR) study on monoindazole-substituted P2 analogues of cyclic urea HIVPIs. The QSAR models revealed an inverted parabolic relationship between biological activity and calculated molar refractivity (CMR). That is, biological activity first decreases with increase in CMR and at a certain minimum point (inversion point) it suddenly changes and increases with further increase in CMR. CMR is a measure of volume-dependent-polarizability and is an indication of the polar interactions between ligand and receptor. The results seem to be best rationalized by larger molecules inducing a change in a receptor unit that allows for a new mode of interaction. Similar QSAR models were also observed for the biological activity of these molecules tested against a panel of mutant viruses including mutant strains with single amino acid substitution (I84V), double amino acid substitutions (I84V/V82F), and multiple amino acid changes corresponding to mutations observed in clinical isolates of patients treated with Ritonavir((R)). Interestingly the inversion points for these mutant strains were found larger than for wild-type. The subtle but significant difference in the inversion point indicates change in the shape and size of the binding pocket. Earlier QSAR studies have shown that the correlation of biological activity with an inverted parabola is an indicative of the 'allosteric interaction' of the ligands with the receptor. This report presents a detail analysis of these observations.
 ...
PMID:Possible allosteric interactions of monoindazole-substituted P2 cyclic urea analogues with wild-type and mutant HIV-1 protease. 1836 96

This study describes the syntheses and characterization of two hydrazino ureas. These fold into a six-membered ring by virtue of the infrequently observed (delta+)N-->C=O (delta-) interaction when solvated by polar protic media. The highly polar functional group resulting from this interaction is hypothesized to especially reproduce electronic but also steric features of the transition states of peptide hydrolysis. The urea moiety constitutes an additional key element of modern HIV-1 protease (HIV PR) inhibitors and is meant to interact with the enzyme flaps. We have developed an efficient, convergent synthetic route to enantiopure compounds that uses CDI to couple two independent building blocks, one derived from amino acids and the other one from easily accessible hydrazines. It is thus amenable to rapid generation of diversity in order to screen for novel HIV PR inhibitors. A complete study using one- and two-dimensional NMR as well as UV spectroscopy confirmed the sole existence of the cyclic constitution of target compounds 7 and 8 in methanol. Total reversal to the linear aldehydic form is observed upon passage to apolar media.
 ...
PMID:Diversity-oriented synthesis of a drug-like system displaying the distinctive N-->C=O interaction. 1863 Aug 76


<< Previous 1 2 3 4 5 6 7 Next >>