The protonation state of the catalytic aspartates in plasmepsin II

Friedman, Ran; Caflisch, Amedeo

doi:10.1016/j.febslet.2007.07.033

Cited by 31 publications

(27 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In fact, EH58 cannot be docked into structures with a smaller S ′ 1 subpocket, e.g., the complex of PM II with the protease inhibitor pepstatin (PDB code 1LS5 [27]). The catalytic dyad was modeled with Asp 214 protonated and Asp 34 negatively charged, according to a previous MD study [29]. All Arg and Lys side chains were positively charged, while Glu and Asp side chains (except Asp 214 ) were negatively charged.…”

Section: Preparation Of the Pm II Structurementioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

Self Cite

View full text Add to dashboard Cite

Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high‐throughput fragment‐based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium‐ and high‐throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.

show abstract

Section: Preparation Of the Pm II Structurementioning

confidence: 99%

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Friedman

Caflisch

2009

ChemMedChem

Self Cite

View full text Add to dashboard Cite

show abstract

“…47,65 Here, we analyze these simulations with respect to the distribution of ions near oppositely charged residues in HIV protease. In addition, the distribution of ions was also studied around a trimer of HET-s, forming a fibril.…”

Section: Ions At the Surface Of Enzymes And Amyloid Fibrilsmentioning

confidence: 99%

Ions and the Protein Surface Revisited: Extensive Molecular Dynamics Simulations and Analysis of Protein Structures in Alkali-Chloride Solutions

Friedman

2011

J. Phys. Chem. B

Self Cite

View full text Add to dashboard Cite

Proteins interact with ions in various ways. The surface of proteins has an innate capability to bind ions, and is also influenced by the screening of the electrostatic potential owing to the presence of salts in the bulk solution. Alkali metal ions and chlorides interact with the protein surface, but such interactions are relatively weak and often transient. In this paper, computer simulations and analysis of protein structures are used to characterize the interactions between ions and the protein surface. The results show that the ion-binding properties of protein residues are highly variable. For example, alkali metal ions are more often associated with aspartate residues than with glutamates, whereas chlorides are most likely to be located near arginines. When comparing NaCl and KCl solutions, it was found that certain surface residues attract the anion more strongly in NaCl. This study demonstrates that proteinsalt interactions should be accounted for in the planning and execution of experiments and simulations involving proteins, particularly if subtle structural details are sought after.

show abstract

“…A recent study reaffirms that the protonation state in the active site influences the ability of scoring methods to determine the native binding pose [63]. Although other classical methods, e.g., MD [61] and MM/Poisson-Boltzmann (PB) surface area [64], can be used for determining the position of hydrogen atoms, the prediction of protonation states should be more robust by means of QM because protonation is related to the formation of the covalent bond between the hydrogen and heavy atom. There are several studies on the determination of protonation states of protease, e.g., -secretase (BACE) [65][66][67][68], plasmepsin [61], and HIV-1 PR [63,69].…”

Section: Protonation Statesmentioning

confidence: 93%

“…The rapid growth of the number of protein structures determined by X-ray crystallography calls for robust methods for determining hydrogen positions, in particular for active site residues in enzymes [29,30,61]. Explicit hydrogen atoms are required for most of the structure based drug design methods [62], e.g., all-atom MM, MD, docking, and electrostatic calculations.…”

Section: Protonation Statesmentioning

confidence: 99%

Quantum Mechanical Methods for Drug Design

Zhou

Huang

Caflisch

2010

CTMC

Self Cite

111

View full text Add to dashboard Cite

Quantum mechanical (QM) methods are becoming popular in computational drug design and development mainly because high accuracy is required to estimate (relative) binding affinities. For low-to medium-throughput in silico screening, (e.g., scoring and prioritizing a series of inhibitors sharing the same molecular scaffold) efficient approximations have been developed in the past decade, like linear scaling QM in which the computation time scales almost linearly with the number of basis functions. Furthermore, QM-based procedures have been used recently for determining protonation states of ionizable groups, evaluating energies, and optimizing molecular structures. For high-throughput in silico screening QM approaches have been employed to derive robust quantitative structure-activity relationship models. It is expected that the use of QM methods will keep growing in all phases of computer-aided drug design and development. However, extensive sampling of conformational space and treatment of solution of macromolecules are still limiting factors for the broad application of QM in drug design.

show abstract

The protonation state of the catalytic aspartates in plasmepsin II

Cited by 31 publications

References 37 publications

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

Ions and the Protein Surface Revisited: Extensive Molecular Dynamics Simulations and Analysis of Protein Structures in Alkali-Chloride Solutions

Quantum Mechanical Methods for Drug Design

Contact Info

Product

Resources

About