Pain remains a significant public health issue with two-thirds of patients achieving little to no pain relief from the myriad of currently available pharmacotherapies and dosing regimens. The use of opioid (e.g. morphine) pharmacotherapies produces several rewarding and reinforcing side effects, which result in the drugs’ diversion to abuse settings. Glial cells have been found to play a critical role in initiating and maintaining increased nociception in response to peripheral nerve injury. The opioids-induced glial cell activation attenuates opioid-induced pain suppression and enhances the development of opioid tolerance and dependence, the drug reward, and other negative side effects such as respiratory depression. We are interested in employing structure-based drug design and high-throughput screening techniques to identify novel small-molecule inhibitors of the cell surface receptors that regulate glial cell activation. The identified agents will potentially serve as therapeutics that suppresses opioid-dependence and tolerance.

Fig (Left) Potentiation of opioid analgesics by targeting the TLR4-mediated glial activation. (A) Opioids activate glia by triggering the signal transduction mediated by the TLR4 (dimeric form in complex with MD-2), resulting in the release of cytokine intercellular mediator, interleukin-1 (IL-1), and suppressing the desired opioid-induced neuronal analgesia effect. (B) In the presence of the antagonists of the TLR4-signaling, such as inhibitors of the critical TLR4 homodimerization or the TLR4/MD-2 interactions, glia stay in the resting state. Opioids (red star) cause analgesia by binding to opioid receptors (orange hexagon). (Right) Designs of peptide antagonists of the TLR4/MD-2 binding based on the TLR4-binding region of MD-2.

The work is being done with The YIN Lab Research (UC@Boulder)

Solvation energy contribution to protein-ligand binding conceptually consists of two different contributions. The first one is collective in nature, comes from the long range interaction of the molecules charges with polar water molecules. The other comes mostly from the short range interactions of the molecules in question with the adjacent layer of the water molecules.

The long range part can be, to a certain extent, be modeled within a continuous electrostatics framework. Recently we have posted a number of improvements to commonly used Generalized Born models. Let us show that GB models may naturally have a good built-in approximation for the surface accessible area for the non-polar contribution calculations.

To do that we take  FSBE model as the example and suggest the following equation for the surface area of a molecule:



where is a coefficient, are the surface tensions associated with the atom types, are the radii of the ions and are the Born radii defined according to the model settings, e.g.



The results of the model surface area differences for 230 protein ligand complexes (the model vs. exact surface data) are presented on the graph. The numbers show an impressive correlation with .

The surface area requires the same power of the Born radii for the evaluation and thus can be implemented both numerically accurate and computationally efficient.

Introduction of drugs puts an evolutionary pressure on viruses and makes the viral proteins evolve. On the other hand, the change in the protein structure should be compatible with the protein function. The degree of the protein sequence conservativity is thus a measure of the structural importance of a particular region on the protein surface. Certain binding sites are evolving and mutate often, certain are not. Finding the most conservative fractions of a target protein sequence can help identify important and druggable binding sites for inhibitors search, find drugs with the least potential for drug resistance development.

Below we provide an analysis of H5N1 neuromidase protein surface next to the tamiflu binding region. The Figure shows the level of protein structure conservation, red portions corresponds to the most conservative residues. A small yellow patch of the pocket has evolved since 1990 and gave way to develop tamiflu resistance.

The analysis shows that in spite of a lot of pressure from the drug application, the virus was not able to change the red part of the pocket. Future drugs should target the binding sites with the least mutable residues.

Surface Charges Generalized Born (SCGB) family of the polar solvation energy caclulation methods is a recently developed approach aimed at getting fast numerical solutions of the Poisson Boltzmann equation in linear time (and memory). SCGB combines the bests of the two worlds: the simplicity of Generalized Born models with the sound physics behind exact continuous electrostatics. Does not only SCGB provide accurate solvation energies for realistic systems, the surface charges obtained in the course of the calculation can be compared directly to those found using a boundary-element version of Poisson equation.

Recently we reported calculation of the Born radii. Now we can use SCGB model expressions for the surface charges density to obtain the solvation energies in linear time as well. The results are represented on the Figure below:

SCGB energies of 233 proteins are calculated first directly (in steps, the horizontal horizontal axis) and then compared with the same energies calculated using FFTw (in steps, the data along the vertical axis). Both energies correlate pretty well aside of the extreme solvation energies region. While the nature of such deviation remains unknown and needs to be fully accounted for, the proof of concept calculation shows the method potential in practical calculations

P.O. Fedichev, L.I. Menshikov
(Submitted on 7 Aug 2008 (v1), last revised 20 Dec 2009 (this version, v3))
We develop a series of approximations to calculate free energy of a polar liquid. We show that long range nature of dipole interactions between the molecules leads to para-electric state instability at low temperatures and to a second-order phase transition. We establish the transition temperature, T_{c}, both within mean field and ring diagrams approximation and show that the ferro-electric transition may play an important role explaining a number of peculiar properties of supercooled water, such as weak singularity of dielectric constant as well as to a large extent anomalous density behavior. Finally we discuss the role of fluctuations, shorter range forces and establish connections with phenomenological models of polar liquids.
Comments: 5 pages, 1 eps figure, density anomaly at T=4C analysis added
Subjects: Statistical Mechanics (cond-mat.stat-mech); Soft Condensed Matter (cond-mat.soft)
Cite as: arXiv:0808.0991v3 [cond-mat.stat-mech]