Biomedical subjects

Ilya Chorny

Publications and source records attributed to Ilya Chorny.

4 recordsLinked to original sources

PubMed2006

Novel human lipoxygenase inhibitors discovered using virtual screening with homology models.

We report the discovery of new, low micromolar, small molecule inhibitors of human platelet-type 12- and reticulocyte 15-lipoxygenase-1 (12-hLO and 15-hLO) using structure-based methods. Specifically, we created homology models of 12-hLO and 15-hLO, based on the structure of rabbit 15-lipoxygenase, for in silico screening of a large compound library followed by in vitro screening of 20 top scoring molecules. Eight of these compounds inhibited either 12- or 15-human lipoxygenase with lower than 100 microM affinity. Of these, we obtained IC50 values for the three best inhibitors, all of which displayed low micromolar inhibition. One compound showed specificity for 15-hLO versus 12-hLO; however, a selective inhibitor for 12-hLO was not identified. As a control we screened 20 randomly selected compounds, of which none showed low micromolar inhibition. The new low-micromolar inhibitors appear to be suitable as leads for further inhibitor development efforts against 12-hLO and 15-hLO, based on the fact their size and chemical properties are appropriate to classify them as drug-like compounds. The models of these protein-inhibitor complexes suggest strategies for future development of selective lipoxygenase inhibitors.

Animals↗

PubMed2005

Surfaces affect ion pairing.

In water, positive ions attract negative ions. That attraction can be modulated if a hydrophobic surface is present near the two ions in water. Using computer simulations with explicit and implicit water, we study how an ion embedded on a hydrophobic surface interacts with another nearby ion in water. Using hydrophobic surfaces with different curvatures, we find that the contact interaction between a positive and negative ion is strongly affected by the curvature of an adjacent surface, either stabilizing or destabilizing the ion pair. We also find that the solvent-separated ion pair (SSIP) can be made more stable than the contacting ion pair by the presence of a surface. This may account for why bridging waters are often found in protein crystal structures. We also note that implicit solvent models do not account for SSIPs. Finally, we find that there are charge asymmetries: an embedded positive charge attracting a negative ion is different than an embedded negative charge attracting a positive ion. Such asymmetries are also not predicted by implicit solvent models. These results may be useful for improving computational models of solvation in biology and chemistry.

Computer Simulation↗

PubMed2005

Hydration shell exchange dynamics during ion transfer across the liquid/liquid interface.

We examine using molecular dynamics simulations the rate and mechanism of water molecules exchange around the Li(+) and Na(+) ions during ion transfer across the interface between water and nitrobenzene. As the ions are transferred from the water to the organic phase, they keep their first hydration shell and an incomplete second shell. The rate of water exchange between the first shell and the rest of the interfacial water molecule decreases during the transfer, which is consistent with an increase in the barrier along the ion-water potential of mean force. While in bulk water the exchange of water molecules around the Li(+) follows an associative (A) or associative interchange (I(a)) type mechanism, the fraction of exchange events of type A increases at the interface. In contrast, while in bulk water the exchange of water molecules around the six coordinated Na(+) hydrated species mainly follows a dissociative mechanism, the situation at the interface involves an equilibrium interchange between the four- and five-coordinated hydrated ion. Simulation of the reversed process, in which the hydrated Li(+) ion is transferred to the aqueous phase, shows the same general behavior as a function of location from the interface.

Cations, Monovalent↗

PubMed2004

Tryptophan 500 and arginine 707 define product and substrate active site binding in soybean lipoxygenase-1.

There is much debate whether the fatty acid substrate of lipoxygenase binds "carboxylate-end first" or "methyl-end first" in the active site of soybean lipoxygenase-1 (sLO-1). To address this issue, we investigated the sLO-1 mutants Trp500Leu, Trp500Phe, Lys260Leu, and Arg707Leu with steady-state and stopped-flow kinetics. Our data indicate that the substrates (linoleic acid (LA), arachidonic acid (AA)), and the products (13-(S)-hydroperoxy-9,11-(Z,E)-octadecadienoic acid (HPOD) and 15-(S)-hydroperoxyeicosatetraeonic acid (15-(S)-HPETE)) interact with the aromatic residue Trp500 (possibly pi-pi interaction) and with the positively charged amino acid residue Arg707 (charge-charge interaction). Residue Lys260 of soybean lipoxygenase-1 had little effect on either the activation or steady-state kinetics, indicating that both the substrates and products bind "carboxylate-end first" with sLO-1 and not "methyl-end first" as has been proposed for human 15-lipoxygenase.

Arginine↗