53 research outputs found
Tautomer Enumeration and Stability Prediction for Virtual Screening on Large Chemical Databases
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Extending pKa prediction accuracy: High-throughput pKa measurements to understand pKa modulation of new chemical series
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Predicting Polypharmacology by Binding Site Similarity: from Kinases to the Protein Universe.
No full textPolypharmacology is receiving increasing attention in the pharmaceutical industry, since finding new targets of a compound not only is useful to anticipate possible side effects, but also to open new therapeutic opportunities. Thus, while system biology and personalized medicine are becoming increasingly important, there is an urgent need to map the inhibition profile of a compound on a large panel of targets by using both experimental and computational methods. This is especially important for kinase inhibitors, given the high similarity at the binding site level for the 518 kinases in the human genome. In this paper we propose and validate a new method to predict the inhibition map of a compound by comparison of binding pockets. We used a subset of the Ambit panel for the validation – 17 inhibitors with Kd measured on 189 kinases – and found that on average 37% of kinases inhibited with Kd < 10 μM were retrieved at 10% ROC enrichment. These results make this method particularly suitable to rationalize and optimize the selectivity profile of a compound, however further applications are envisioned. The study was extended to explore all the proteins in the PDB by using, as queries, pockets occupied by compounds of biological interest (ATP and various marketed drugs). The profiling of compounds against the protein universe revealed that striking structural similarities at the sub-pocket level (RMSD < 0.5 Å) may also occur among targets with different folds, which can be exploited not only to predict off-target effects, but also to design novel inhibitors for the target of interest
Tautomer Preference in PDB Complexes and its Impact on Structure-Based Drug Discovery
No full textTautomer enrichment is a key step of ligand preparation prior to virtual screening. In this paper, we have investigated how tautomer preference in various media (water, gas phase, and crystal) compares to tautomer preference at the active site of the protein by analyzing the different possible H-bonding contacts for a set of 13 tautomeric structures. In addition, we have explored the impact of four different protocols for the enumeration of tautomers in virtual screening by using Flap, Glide, and Gold as docking tools on seven targets of the DUD data set. Excluding targets in which the binding does not involve tautomeric atoms (HSP90, p38, and VEGFR2), we found that the average receiver operating characteristic curve enrichment at 10% was 0.25 (Gold), 0.24 (Glide), and 0.50 (Flap) by considering only tautomers predicted to be unstable in water versus 0.41 (Gold), 0.56 (Glide), 0.51 (Flap) by limiting the enumeration process only to the predicted most stable tautomer. The inclusion of all tautomers (stable and unstable) yielded slightly poorer results than considering only the most stable form in water
Computational studies of cell-penetrating peptides interactions with complex membranes models
No full textMembrane active peptides with the ability to cross the plasma membrane represent a promising class of therapeutic compounds. However, translocation efficacy and membrane toxicity of these peptides appear correlated and a better understanding of their mechanisms of action is needed to achieve the desired effect. Here, a range of coarse grain molecular dynamics simulations have been performed to systematically investigate the interactions of such cell-penetrating peptides (CPPs) with biologically relevant membranes. Challenges associated to the development of a suitable asymmetric mammalian membrane model demonstrated the importance of lipid species distribution on the bilayer mechanical properties, as well as the effect of coarse graining on its electrostatic properties. However, simulations successfully discriminated between two CPPs, penetratin and transportan, and were consistent with the experimental data available for these. The results obtained suggest that the ability of transportan peptides to aggregate into flexible, dynamic, transmembrane bundles is responsible for their relative membrane toxicity. The stability and structure of these aggregates, as well as the extent of the bilayer perturbations they induced, were shown to depend on the membrane composition and asymmetry, thus providing a molecular basis to explain how the toxicity of CPPs is modulated by membranes. In particular, bilayer destabilisation was enhanced by the presence of anionic lipids and hampered by that of cholesterol. Transportan aggregates were also observed to trigger lipid flip-flops above a certain size and a new pathway for such events, not relying on the formation of water defects, was characterised
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