3B03
Application of Raman Spectroscopy from MOFs to Drug Discovery
Chandrabhas Narayana
Chemistry and Physics of Materials Unit & School of Advanced Materials,
Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bangalore
560064,India
Raman spectroscopy has been a very important spectroscopic tool, but with the advent ofnano-technology, it has gained enormous potential. Unfortunately, many researchers have notused the potential of Raman spectroscopy except using it as a characterization tool. Due to theease of doing Raman spectroscopy and its ability to give not only vibrational properties ofmolecules and solids but also its inter connection with electronic states and spin states gives it
an edge over many other spectroscopic tools available. One can use Raman to investigate themicroscopic origin of the properties of the molecules and solids. In this respect this talk aims
to emphasis the use of Raman spectroscopy to investigate the microscopic origin of gas
adsorption in Metal Organic Frameworks (MOFs) and understanding the small molecule
therapeutic protein interaction in combination with Molecular Dynamics (MD) simulations toassist in Drug Discovery.
An unusual CO2 adsorption behavior is seen in fluoro-functionalized MOF{[Zn(SiF6)(pyz)2]_2MeOH}n (1) with a 1D channel system, which is made up of pyrazine andSiF6 2- moieties. Surprisingly, desolvated 1 (1') adsorbs higher amounts of CO2 at 298 K thanat 195 K, which is in contrast to the usual trend. This unusual observation was revealed using
Raman spectroscopic and theoretical studies. Raman spectroscopy shows that upon
desolvating the pyrazine rings are slanted in 1' and reaches an angle of 17.280 with respect tothe (200) Zn(II)–Si plane at low temperature. This block the channel windows at low
temperature leading to reduce the uptake amount [1].
In another example, we have used zeolitic imidazolate framework ZIF-8, where even though
the channel is equal to the kinetic diameter of CO2 it adsorbs larger molecules such as N2 andCH4, but not CO2. Raman spectroscopy was used to investigate molecular level changes in
the ZIF-8 (a prototypical zeolite-like porous metal organic framework) as a function oftemperature. Temperature dependent Raman spectra suggest that at low temperature thesoftening of the C−H stretching frequencies is due to the decrease in steric hindrance between
the methyl groups of methyl imidazole. The larger separation between the methyl groups
lining the channel opens the window for increased nitrogen and methane uptake attemperatures below 153 K. Since CO2 solidifies at 195 K, it is hindered from entering thechannel due to blocking done by the methyl group. The appearance of Raman bands at 2323
cm−1 and 2904 cm−1 at or below 153 K in ZIF-8 are characteristic signatures of the adsorbed
nitrogen and methane gases respectively. Nanoscale ZIF-8 uptakes more molecules than bulk
ZIF-8, and as a result we could provide evidence for encaged CO2 at 203 K yielding its
Raman mode at 1379 cm−1 [2].
In the recent years, surface enhanced Raman spectroscopy (SERS) has become an important
tool to detect trace amount of analytes and has seen many technologies being developed.
Since therapeutically important proteins in biologically important conditions are usuallyfound to be in nano-Molar concentration, we have used SERS to study several proteins withan intent to understand the drug protein interaction for potential drug screening or drug
discovery. As an example, we have taken the case of a selective inhibition of oncogenic
Aurora A Kinase by Felodipine. This is important as Aurora A Kinase is over expressed inmost of the Tumours, but it has a very similar structure to Aurora B Kinase with only 4 aminoacid residues different in the catalytic site for ATP binding. It is very difficult to get any drug
to selectively bind to Aurora A Kinase due to this fact. We have used SERS and MD
simulations to show that Felodipine takes advantage of a extra hystidine amino acid in thehinge region of the Aurora A Kinase of human enzyme to selectively bind to it on the surfaceof the Aurora A Kinase leading to reduction of access to the catalytic region for ATP binding,leading to the inhibition. Mutagenesis experiments suggest Tyr-212 is the important aminoacid helping in the binding of Felodipine. We have demonstrated this through bind studies ofReversine which binds at the catalytic cite of both Aruora A/Aurora B kinase [3][References][1] P. Kanoo et al. Chemical Communications 48, 8487 (2012).
[2] Gayatri Kumari et al. Journal of Physical Chemistry A 117, 11006 (2013).
[3] D. Karthigeyan et al. Proceedings of National Academy of Sciences 111, 10416 (2014).