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)

The importance of the active site region aspartyl residues 25 and 29 of the mature HIV-1 protease (PR) for the binding of five clinical and three experimental protease inhibitors [symmetric cyclic urea inhibitor DMP323, nonhydrolyzable substrate analog (RPB) and the generic aspartic protease inhibitor acetyl-pepstatin (Ac-PEP)] was assessed by differential scanning calorimetry. DeltaT(m) values, defined as the difference in T(m) for a given protein in the presence and absence of inhibitor, for PR with DRV, ATV, SQV, RTV, APV, DMP323, RPB, and Ac-PEP are 22.4, 20.8, 19.3, 15.6, 14.3, 14.7, 8.7, and 6.5 degrees C, respectively. Binding of APV and Ac-PEP is most sensitive to the D25N mutation, as shown by DeltaT(m) ratios [DeltaT(m)(PR)/DeltaT(m)(PR(D25N))] of 35.8 and 16.3, respectively, whereas binding of DMP323 and RPB (DeltaT(m) ratios of 1-2) is least affected. Binding of the substrate-like inhibitors RPB and Ac-PEP is nearly abolished (DeltaT(m)(PR)/DeltaT(m)(PR(D29N)) > or = 44) by the D29N mutation, whereas this mutation only moderately affects binding of the smaller inhibitors (DeltaT(m) ratios of 1.4-2.2). Of the nine FDA-approved clinical HIV-1 protease inhibitors screened, APV, RTV, and DRV competitively inhibit porcine pepsin with K(i) values of 0.3, 0.6, and 2.14 microM, respectively. DSC results were consistent with this relatively weak binding of APV (DeltaT(m) 2.7 degrees C) compared with the tight binding of Ac-PEP (DeltaT(m) > or = 17 degrees C). Comparison of superimposed structures of the PR/APV complex with those of PR/Ac-PEP and pepsin/pepstatin A complexes suggests a role for Asp215, Asp32, and Ser219 in pepsin, equivalent to Asp25, Asp25', and Asp29 in PR in the binding and stabilization of the pepsin/APV complex.
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PMID:Interactions of different inhibitors with active-site aspartyl residues of HIV-1 protease and possible relevance to pepsin. 1895 11

HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.
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PMID:Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir. 2969 1

HIV-1 protease (HIV PR) is considered as one of the most attractive targets for the treatment of HIV and the impact of flap dynamics of HIV PR on the binding affinities of protease inhibitors (PIs) is a crucial ongoing research field. Recently, our research group evaluated the binding affinities of different FDA approved PIs against the South African HIV-1 subtype C (C-SA) protease (PR). The CSA-HIV PR displayed weaker binding affinity for most of the clinical PIs compared to HIV-1 B subtype for West and Central Europe, the Americas. In the current work, the flap dynamics of four different systems of HIV-1 C-SA PR complexed to FDA approved second generation PIs and its impact on binding was explored over the molecular dynamic trajectories. It was observed that the interactions of the selected drugs with the binding site residues of the protease may not be the major contributor for affinity towards PIs. Various post-MD analyses were performed, also entropic contributions, solvation free energies and hydrophobic core formation interactions were studied to assess how the flap dynamics of C-SA PR which is affected by such factors. From these contributions, large van der Waals interactions and low solvation free energies were found to be major factors for the higher activity of ATV against C-SA HIV PR. Furthermore, a comparatively stable hydrophobic core may be responsible for higher stability of the PR flaps of the ATV complex. The outcome of this study provides significant guidance to how the flap dynamics of C-SA PR is affected by various factors as a result of the binding affinity of various protease inhibitors. It will also assist with the design of potent inhibitors against C-SA HIV PR that apart from binding in the active site of PR can interacts with the flaps to prevent opening of the flaps resulting in inactivation of the protease.
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PMID:Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA-approved inhibitors: MD study. 3000 68