Not only our recently introduced surface charges generalized Born (SCGB) models prove to be reasonable in terms of providing solutions to Poisson Boltzmann equation in complicated geometries, such as biomolecules. By getting rid of the standard expression for the solvation energy we are able to formulate SCGB models in terms of a fast algorithm using FFT. The comparison between the Born radii calculated with the help of the fast method and the standard approach is presented below:

The calculation was performed for 2ht7 H1N1 neuromidase protein. The radii match over a broad range of the atoms locations within the protein. The fast method involves an (large) computational overhead due to FFT calculation and breaks even with the usual approach for any molecule exceeding about a thousand atoms.

Up to now, there have been at least two schools of thoughts among those trying to calculate electrostatics part of solvation energies. Half of the folks believe that only an exact solution of the Poisson equation can be better than the solution of the Poisson equation. The other half believes that though the exact solution of the Poisson equation can be obtained, it is too slow and numerically unstable. Here in Quantum we attempt to give Generalized Born models almost infinite credit of trust and push for a direct link between the Poisson equation solutions and Generalized Born models.

The missing link between the two worlds is established by the equation linking the Born radii with the water polarization charges on a molecular interface. If the surface charges are then interpreted on their own, we can calculate the solvation energy using its direct definition, rather than an approximate Born formula. The question is of course if it all works in real life.

To proof the concept we attempted the calculation of the solvation energies for about 580 proteins from our Quantum Pharmaceuticals target list of proteins with available 3D structure. The results obtained with 4 different types of Surface Charges Generalized Born (SCGB) models are compared with the Surface Electrostatics solutions of the Poisson eqaution and are summarized below:

Here the surface electrostatics solvation energies are measured along the horizontal axis, the vertical axis is used for the SCGB solvation energies values. The green dots represent SCGB model with FSBE radii, yellow and red dots are SCGB models with respectively. All the three models give exact solvation energies for an arbitrary system of charges within a shpere and cope fairly well with the realistic proteins. SCGB with standard CFA Born radii (the blue dots) are completely off. Given tremendous speed advantage of SCGB models over SE we end up with an approximation worth to be employed!

As part of recent efforts to expand cooperation in health, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) is interested in learning more about the spectrum of biomedical research and expertise in the Russian Federation. In particular, efforts focusing on detection of drug resistant tuberculosis and discovery / development of new drugs to treat tuberculosis are among the highest research priorities.

Steven Smith, Director of the NIH/NIAID Office of Global Research, Dr Barbara Laughton (NIH/NIAID) and Gail Cassell (Eli Lilly) visited the ISTC offices in Moscow on Tuesday, 17 November 2009. The goal of the meeting was to present the respective programs and to better understand the science underway for new antibiotic development by meeting with several renowned investigators in Moscow during their visit at ISTC. As a part of the meeting Quantum delivered a presentation concerning our anti-tuberculosis drug candidate.

NIH distributes $170M in grants among non-US research organizations every year. Most of the money come to the US collaborators, though there are grants available to non-US residents as well (though fewer in numbers). NIAID leads the anti-tuberculosis effort and is involved in a great number of collaborative projects. The latest project is performed together with Bill&Melinda Gates foundation and resulted in creation of a comprehensive online TB research database http://tbdb.org. NIAID funds screening of compound libraries (the statistics shows roughly 1% hit rate, AID 1949: 101k compounds tested, 1594active; AID 1626: 215k compounds tested, 2044compounds found active).

Eli Lilly has also presented its non-profit anti-TB initiative. Gail Cassell of EL highlighted a scary situation with XDR TB, originally identified in 2006 and by now comprising up to 30-50% cases in some regions of South Africa and India. 30% HIV-positive patients with XDR TB are dead within a few months. The world's R&D spendings against TB are around $150M/year. With new drugs costs approaching 1B, the current budget hardly allows for getting a single new drug in 5-10years. This is in spite of the fact that XDR TB treatment would require a cocktail of a few novel and highly efficient drugs.

QUANTUM drug discovery platform is developed with the idea of bringing down the drug discovery costs and may well be the lacking tool to bring up the long awaited, cheap and effective medications against TB

We have recently established a relation between the Generalized Born methods and finite elements surface electrostatics. Indeed, if the Generalized Born solvation energy is interpreted as a (though approximate) definition of the reaction field potential, then the boundary condition defines the surface chages in terms of the Born radii of the charges:

Once the surface charges are known, we can try to interpret them as approximate water polarization charges and express the solvation energy in terms of the reaction field potential of the surface charges:



The expression comes from classic electrostatics and does not depend on the definition of the Born radii. There are many ways to get the radii, three of them give exact result for a (system of) charge(s) within a spherical cavity. One of them,



is special and guarantees the overall neutrality of the system: . To see the idea works we took a realistic protein (H1N1 neuromidase, pdb accession code 2ht7) and calculated Born radii of each of the atoms by charging it with a single charge and calculating the solvation energy either exactly (using a finite element method) and approximately, using Eq.(1) - (2). The Born radii are obtained from the definition and correlated against each other on the graph below:



The correlation shows that although the two quantities are not exactly similar, the surface charges Generalized Born radii are nearly identical to exact ones when the radii are small (the atoms near the protein surface). The correlation fails for deeply buried atoms, as it often happens to Born models. What remains to be seen though if the correlation holds, at least approximately, for a multiply charged molecules (see our future posts).

Normally siRNA do not penetrate cell membranes without transfection reagents. In Quantum Pharmaceutical we developed a new nanoscale complex with ability to transport siRNA over cell membranes of a cancer cell. In experiments with fluorescent siRNA molecules coupled with our proprietory transport system we conformed the ability of the complex to penetrate the cell membrane already in nanomolar concentration range. To demonstrate that we performed the experiments on lung cancer cells A549 and H1299 incubated with 20 nM concentration of our lead compound QP-654 and observed after overnight incubation.

The graphs above show uptake of the flourescent siRNA complex by the cancer cells. The left upper picture represents nuclear staining of A549 cells with Hoechst dye. The right upper picture represent uptake of fluorescent siRNA complex by the cancer cells. The lower picture corresponds to superposition of upper pictures and indicates the accumulation of the siRNA-containing complex in the cancer sells and thus proves the efficacy of the transport system.