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

Water-soluble lignin extracted from natural sources and dehydrogenated polymers of p-coumaric acid and ferulic acid inhibited HIV-1 protease activity. The dehydrogenated polymers, which are thought to be model compounds for lignin, were synthesized and fractionated into four ranges of molecular mass by ultra-filtration: i.e., over 30 kDa, 30-10 kDa, 10-1 kDa and 1 kDa-500 Da. All of these fractions had HIV-1 protease inhibitory activity. The anti-HIV-1 effect of the smallest mass fractions of the dehydrogenated polymers (1 kDa-500 Da) was also tested, and it was found that these fractions inhibited the replication of HIV-1 in MT-4 cells.
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PMID:HIV-1 protease inhibition and anti-HIV effect of natural and synthetic water-soluble lignin-like substances. 1066 53

A computer model of a noncovalent complex of HIV-1 aspartyl protease with substrate-like inhibitor JG-365 was a priori constructed by using the approaches of theoretical conformational analysis and molecular mechanics. The root mean square deviation of the calculated conformation of the inhibitor from the X-ray diffraction analysis data was 0.87 A. These results enabled the a priori calculation of the structure of noncovalent complex of HIV-1 protease with a hexapeptide fragment of its native specific substrate Ser-Gln-Asn-Tyr-Pro-Ile-Val. The only possible orientation of the cleavable peptide bond in this and the nucleophilic water molecule relative to the catalytically active Asp residues of the enzyme (Asp25 and Asp125) was found that provides for the chemical transformation of the substrate to a tetrahedral intermediate. An action mechanism of enzymes of this class was proposed on the basis of the analysis of calculated distances. We showed that neither steric distortion of the cleavable bond nor the formation of unfavorable contacts in molecules of the enzymes and their substrates accompany the optimum orientation of substrate molecules at the active sites of HIV-1 aspartyl proteases and rhizopuspepsin.
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PMID:[Mechanism of aspartyl proteinase action. VII. Noncovalent complexes of HIV-1 aspartyl proteinase with substrate and substrate-like inhibitors]. 1073 51

The new chemical entity CGP 70726, a very poorly water-soluble HIV-1 protease inhibitor, was incorporated into pH-sensitive nanoparticles and microparticles made of the poly(methacrylic acid-co-ethylacrylate) copolymer Eudragit((R)) L100-55. The particles were characterized in terms of morphology, size distribution, drug loading, production yield and dispersion state of the drug inside the polymeric matrices. Aqueous dispersions of the particles were administered orally to Beagle dogs against a suspension of free drug (control formulation) all at a dose of 100 mg/kg. Oral administration was conducted in the absence and presence of food. Plasma concentrations and pharmacokinetic parameters were determined within 8 h post-dose. While no measurable absorption of the drug resulted after administration of the control formulation, substantial systemic exposure to the compound was obtained with both kinds of pH-sensitive formulations. The selective release of CGP 70726 in a highly dispersed/amorphous state and creation of high concentrations close to its absorption site was thought to account for this positive result. The largest areas under the plasma concentration-time curve (AUC) were obtained in the fasted state, with slightly better performance of the microparticles over the nanoparticles, in both nutritional states (7.8+/-1.5 versus 5.8+/-0. 8 micromol.h/l in the fasted state; 4.4+/-1.4 versus 2.00+/-0.5 micromol.h/l in the fed state). With these results, the potential of pH-sensitive particles for the oral delivery of HIV-1 protease inhibitors with low water solubility was confirmed.
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PMID:Oral bioavailability of a poorly water soluble HIV-1 protease inhibitor incorporated into pH-sensitive particles: effect of the particle size and nutritional state. 1092 37

The crystal structure of an actual HIV-1 protease-substrate complex is presented at 2.0 A resolution (R-value of 19.7 % (R(free) 23.3 %)) between an inactive variant (D25N) of HIV-1 protease and a long substrate peptide, Lys-Ala-Arg-Val-Leu-Ala-Glu-Ala-Met-Ser, which covers a full binding epitope of capsid(CA)-p2, cleavage site. The substrate peptide is asymmetric in both size and charge distribution. To accommodate this asymmetry the two protease monomers adopt different conformations burying a total of 1038 A(2) of surface area at the protease-substrate interface. The specificity for the CA-p2 substrate peptide is mainly hydrophobic, as most of the hydrogen bonds are made with the backbone of the peptide substrate. Two water molecules bridge the two monomers through the loops Gly49-Gly52 (Gly49'-Gly52') and Pro79'-Val82' (Pro79-Val82). When other complexes are compared, the mobility of these loops is correlated with the content of the P1 and P1' sites. Interdependence of the conformational changes allows the protease to exhibit its wide range of substrate specificity.
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PMID:How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease. 1096 16

KNI-272 is a powerful HIV-1 protease inhibitor with a reported inhibition constant in the picomolar range. In this paper, a complete experimental dissection of the thermodynamic forces that define the binding affinity of this inhibitor to the wild-type and drug-resistant mutant V82F/184V is presented. Unlike other protease inhibitors, KNI-272 binds to the protease with a favorable binding enthalpy. The origin of the favorable binding enthalpy has been traced to the coupling of the binding reaction to the burial of six water molecules. These bound water molecules, previously identified by NMR studies, optimize the atomic packing at the inhibitor/protein interface enhancing van der Waals and other favorable interactions. These interactions offset the unfavorable enthalpy usually associated with the binding of hydrophobic molecules. The association constant to the drug resistant mutant is 100-500 times weaker. The decrease in binding affinity corresponds to an increase in the Gibbs energy of binding of 3-3.5 kcal/mol, which originates from less favorable enthalpy (1.7 kcal/mol more positive) and entropy changes. Calorimetric binding experiments performed as a function of pH and utilizing buffers with different ionization enthalpies have permitted the dissection of proton linkage effects. According to these experiments, the binding of the inhibitor is linked to the protonation/deprotonation of two groups. In the uncomplexed form these groups have pKs of 6.0 and 4.8, and become 6.6 and 2.9 in the complex. These groups have been identified as one of the aspartates in the catalytic aspartyl dyad in the protease and the isoquinoline nitrogen in the inhibitor molecule. The binding affinity is maximal between pH 5 and pH 6. At those pH values the affinity is close to 6 x 10(10) M(-1) (Kd = 16 pM). Global analysis of the data yield a buffer- and pH-independent binding enthalpy of -6.3 kcal/mol. Under conditions in which the exchange of protons is zero, the Gibbs energy of binding is -14.7 kcal/mol from which a binding entropy of 28 cal/K mol is obtained. Thus, the binding of KNI-272 is both enthalpically and entropically favorable. The structure-based thermodynamic analysis indicates that the allophenylnorstatine nucleus of KNI-272 provides an important scaffold for the design of inhibitors that are less susceptible to resistant mutations.
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PMID:Thermodynamic dissection of the binding energetics of KNI-272, a potent HIV-1 protease inhibitor. 1104 25

Three-dimensional structure of an asymmetrically mutated (C95M) tethered human immunodeficiency virus type 1 protease enzyme (HIV-1 PR) has been determined in an unliganded form using X-ray diffraction data to 1.9 A resolution. The structure, refined using X-PLOR to an R factor of 19.5%, is unexpectedly similar to the ligand-bound native enzyme, rather than to the ligand-free native enzyme. In particular, the two flaps in the tethered dimer are in a closed configuration. The environments around M95 and C1095 are identical, showing no structural effect of this asymmetric mutation at position 95. Oxidation of Cys1095 has been observed for the first time. There is one well-defined water molecule that hydrogen bonds to both carboxyl groups of the essential aspartic acids in the active site. Proteins 2001;43:57-64.
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PMID:1.9 A x-ray study shows closed flap conformation in crystals of tethered HIV-1 PR. 1117 Feb 14

A method (FILO, Field Interaction Ligand Optimization) for obtaining the optimal molecular interaction field was developed on the basis of the Simplex optimization procedure applied to a matrix of interaction energies obtained by performing a GRID computation on a suitable data set. The FILO procedure was tested on a set of nine HIV-1 protease inhibitors with known crystal structures. The results of FILO consist of the optimal molecular interaction field of a putative new ligand with optimal binding affinity. The final FILO model yields R2 and R2(CV) values of 0.993 and 0.936, respectively, and finds eight negative and four positive interaction nodes for the OH probe taken as an example. The eight H bonding interactions pointed out by FILO identified well the binding site AA-residues Gly A27, Asp A29, water 501, Gly B48 and Asp A25 of HIV-1 protease.
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PMID:FILO (field interaction ligand optimization): a simplex strategy for searching the optimal ligand interaction field in drug design. 1121 19

Crystallization conditions for an HIV-1 protease-inhibitor complex were optimized to produce crystals suitable for X-ray diffraction experiments. The X-ray structure of the HIV-1 protease complex was solved and refined at 3.1 A resolution. In contrast to Saquinavir, the mimetic hydroxy group of the inhibitor Boc-Phe-Psi[(S)-CH(OH)CH(2)NH]-Phe-Glu-Phe-NH(2) is placed asymmetrically with respect to the non-crystallographic twofold axis of the protease dimer so that hydrogen bonds between the amino group of the inhibitor and the catalytic aspartates can be formed. The inhibitor binds in the centre of the active site by a compact network of hydrogen bonds to Gly27, Gly127, Asp25, Asp125 and via the buried water molecule W301 to Ile50 and Ile150.
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PMID:A distinct binding mode of a hydroxyethylamine isostere inhibitor of HIV-1 protease. 1122 36

Emergence of drug-resistant mutants of HIV-1 protease is an ongoing problem in the fight against AIDS. The mechanisms governing resistance are both complex and varied. We have determined crystal structures of HIV-1 protease mutants, D30N, K45I, N88D, and L90M complexed with peptide inhibitor analogues of CA-p2 and p2-NC cleavage sites in the Gag-pol precursor in order to study the structural mechanisms underlying resistance. The structures were determined at 1.55-1.9-A resolution and compared with the wild-type structure. The conformational disorder seen for most of the hydrophobic side-chains around the inhibitor binding site indicates flexibility of binding. Eight water molecules are conserved in all 9 structures; their location suggests that they are important for catalysis as well as structural stability. Structural differences among the mutants were analyzed in relation to the observed changes in protease activity and stability. Mutant L90M shows steric contacts with the catalytic Asp25 that could destabilize the catalytic loop at the dimer interface, leading to its observed decreased dimer stability and activity. Mutant K45I reduces the mobility of the flap and the inhibitor and contributes to an enhancement in structural stability and activity. The side-chain variations at residue 30 relative to wild-type are the largest in D30N and the changes are consistent with the altered activity observed with peptide substrates. Polar interactions in D30N are maintained, in agreement with the observed urea sensitivity. The side-chains of D30N and N88D are linked through a water molecule suggesting correlated changes at the two sites, as seen with clinical inhibitors. Structural changes seen in N88D are small; however, water molecules that mediate interactions between Asn88 and Thr74/Thr31/Asp30 in other complexes are missing in N88D.
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PMID:Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes. 1134 Jun 61

Ritonavir is an HIV-1 protease inhibitor that is often used to improve the systemic availability of concurrently administered protease inhibitors by impairing their metabolism through cytochrome P450 (CYP) 3A4. Pharmacodynamic relationships between plasma ritonavir concentrations and efficacy and toxicity have also been described. To date, published high-performance liquid chromatographic (HPLC) methods for the determination of ritonavir in human plasma are often complex, requiring the use of a buffered mobile phase that contains amine-modifiers (i.e. diethylamine, triethylamine). In the method herein, ritonavir was precipitated with acetonitrile plus barium hydroxide and zinc sulphate. Chromatographic separation was accomplished using a C-18 base-deactivated (250 x 4.6 mm I.D., 5 atm particle size) analytic column with a mobile phase composed of acetonitrile:water (52:48, v/v). Quantification was performed at 239 nm. Calibration curves were linear from 0.5-25 microg/ml (R2 > 0.999); percent errors, as a measure of accuracy, were < 12.7%. Intra- and inter-assay relative standard deviations (RSD) were below 12.8%. This method provides a rapid and simple means for the accurate and precise analysis of ritonavir in human plasma. Furthermore, the assay requires neither the use of a buffered mobile phase adjusted to a specific pH, nor the addition of amine modifiers. This method has been successfully used to determine plasma ritonavir concentrations in drug interaction studies.
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PMID:Rapid and sensitive high-performance liquid chromatographic method for the determination of ritonavir in human plasma. 1156 87


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