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Exploration of multiple Sortase A protein conformations in virtual screening.

ABSTRACT: Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the ?6/?7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds.

SUBMITTER: Gao C

PROVIDER: S-EPMC4742773 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Exploration of multiple Sortase A protein conformations in virtual screening.

Gao Chunxia C Uzelac Ivana I Gottfries Johan J Eriksson Leif A LA

Scientific reports 20160205

Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as ...[more]

PMID: 26846342

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Project description:Protein conformational change is an important consideration in ligand-docking screens, but it is difficult to predict. A simple way to account for protein flexibility is to soften the criterion for steric fit between ligand and receptor. A more comprehensive but more expensive method would be to sample multiple receptor conformations explicitly. Here, these two approaches are compared. A "soft" scoring function was created by attenuating the repulsive term in the Lennard-Jones potential, allowing for a closer approach between ligand and protein. The standard, "hard" Lennard-Jones potential was used for docking to multiple receptor conformations. The Available Chemicals Directory (ACD) was screened against two cavity sites in the T4 lysozyme. These sites undergo small but significant conformational changes on ligand binding, making them good systems for soft docking. The ACD was also screened against the drug target aldose reductase, which can undergo large conformational changes on ligand binding. We evaluated the ability of the scoring functions to identify known ligands from among the over 200 000 decoy molecules in the database. The soft potential was always better at identifying known ligands than the hard scoring function when only a single receptor conformation was used. Conversely, the soft function was worse at identifying known leads than the hard function when multiple receptor conformations were used. This was true even for the cavity sites and was especially true for aldose reductase. To test the multiple-conformation method predictively, we screened the ACD for molecules that preferentially docked to the expanded conformation of aldose reductase, known to bind larger ligands. Six novel molecules that ranked among the top 0.66% of hits from the multiple-conformation calculation, but ranked relatively poorly in the soft docking calculation, were tested experimentally for enzyme inhibition. Four of these six inhibited the enzyme, the best with an IC(50) of 8 microM. Although ligands can get better scores in soft docking, the same is also true for decoys. The improved ranking of such decoys can come at the expense of true ligands.

Project description:The protein docking problem has two major aspects: sampling conformations and orientations, and scoring them for fit. To investigate the extent to which the protein docking problem may be attributed to the sampling of ligand side-chain conformations, multiple conformations of multiple residues were calculated for the uncomplexed (unbound) structures of protein ligands. These ligand conformations were docked into both the complexed (bound) and unbound conformations of the cognate receptors, and their energies were evaluated using an atomistic potential function. The following questions were considered: (1) does the ensemble of precalculated ligand conformations contain a structure similar to the bound form of the ligand? (2) Can the large number of conformations that are calculated be efficiently docked into the receptors? (3) Can near-native complexes be distinguished from non-native complexes? Results from seven test systems suggest that the precalculated ensembles do include side-chain conformations similar to those adopted in the experimental complexes. By assuming additivity among the side chains, the ensemble can be docked in less than 12 h on a desktop computer. These multiconformer dockings produce near-native complexes and also non-native complexes. When docked against the bound conformations of the receptors, the near-native complexes of the unbound ligand were always distinguishable from the non-native complexes. When docked against the unbound conformations of the receptors, the near-native dockings could usually, but not always, be distinguished from the non-native complexes. In every case, docking the unbound ligands with flexible side chains led to better energies and a better distinction between near-native and non-native fits. An extension of this algorithm allowed for docking multiple residue substitutions (mutants) in addition to multiple conformations. The rankings of the docked mutant proteins correlated with experimental binding affinities. These results suggest that sampling multiple residue conformations and residue substitutions of the unbound ligand contributes to, but does not fully provide, a solution to the protein docking problem. Conformational sampling allows a classical atomistic scoring function to be used; such a function may contribute to better selectivity between near-native and non-native complexes. Allowing for receptor flexibility may further extend these results.

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Exploration of multiple Sortase A protein conformations in virtual screening.

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Exploration of multiple Sortase A protein conformations in virtual screening.

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