13 research outputs found
Structural Basis for HTLV 1 Protease Inhibition by the HIV 1 Protease Inhibitor Indinavir
Privileged Structures Meet Human T Cell Leukemia Virus 1 HTLV 1 C 2 Symmetric 3,4 Disubstituted Pyrrolidines as Nonpeptidic HTLV 1 Protease Inhibitors
3,4-disubstituted
pyrrolidines originally designed to inhibit the
closely related HIV-1 protease were evaluated as privileged structures
against HTLV-1 protease (HTLV-1 PR). The most potent inhibitor of
this series exhibits two-digit nanomolar affinity and represents,
to the best of our knowledge, the most potent nonpeptidic inhibitor
of HTLV-1 PR described so far. The X-ray structures of two representatives
bound to HTLV-1 PR were determined, and the structural basis of their
affinity is discussed
Structural and Kinetic Analysis of Pyrrolidine Based Inhibitors of the Drug Resistant Ile84Val Mutant of HIV 1 Protease
Human immunodeficiency virus HIV protease is a well established drug target in HIV chemotherapy. However, continuously increasing resistance towards approved drugs inevitably requires the development of new inhibitors preferably showing no susceptibility against resistant HIV protease strains. Recently, symmetric pyrrolidine 3,4 bis N benzyl sulfonamides have been developed as a new class of HIV 1 protease inhibitors. The most promising candidate exhibited a Ki of 74 nM towards a wild type protease. Herein, we report the influence of the active site mutations Ile50Val and Ile84Val on these inhibitors by structural and kinetic analysis. Although the Ile50Val mutation leads to a significant decrease in affinity for all compounds in this series, they retain or even show increased affinity towards the important Ile84Val mutation. By detailed analysis of the crystal structures of two representatives in complex with wild type and mutant proteases, we were able to elucidate the structural basis of this phenomeno
Structure Guided Design of C2 Symmetric HIV 1 Protease Inhibitors Based on a Pyrrolidine Scaffold
Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus replication process. By use of pyrrolidine as core structure, symmetric 3,4 bis N alkylsulfonamides were designed and synthesized enantioselectively from d amp; 8722; tartaric acid as a new class of HIV protease inhibitors. Structure guided design using the cocrystal structure of an initial lead as starting point resulted in a second series of inhibitors with improved affinity. The binding modes of four representatives were determined by X ray crystallography to elucidate the underlying factors accounting for the SAR. With this information for further rational design, the combination of suitable side chains resulted in a final inhibitor showing a significantly improved affinity of Ki 74 n
Two Solutions for the Same Problem Multiple Binding Modes of Pyrrolidine Based HIV 1 Protease Inhibitors
Structural basis for catalysis and substrate specificity of a 3C-like cysteine protease from a mosquito mesonivirus
Molecular basis of virus replication, viral pathogenesis and antiviral strategie
Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?
The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values
Tracing Binding Modes in Hit to Lead Optimization Chameleon Like Poses of Aspartic Protease Inhibitors
Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure–activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation