Title:	Computational Biophysics - Drug-Membrane interactions, Photochemistry and Enzymatic reactions.
DNr:	SNIC 011/08-17
Project Type:	SNIC Large Compute
Principal Investigator:	Leif Eriksson <leif.eriksson@chem.gu.se>
Duration:	2008-07-01 – 2009-06-30
Classification:	151101 151202 151401
Homepage:	http://www.oru.se/biophyschem
Keywords:	membrane, photodynamic therapy, photodegradation, drug, enzymatic catalysis

Abstract

We aim to use quantum chemistry and molecular dynamics tools, to explore mechanisms and develop new pharmaceuticals for use in photodynamic therapy (cancer treatment), and novel non-steroid anti-inflammatory drugs (NSAIDs) without phototoxic side effects. More specifically, our project aims at: (i) Exploring the biosynthetic route of protoporphyrin IX (PpIX) from 5-aminolevulinic acid or derivatives thereof, as target in PDT. This will involve the modelling of several enzymatic processes. (ii) Search for new inhibitors to Ferrochelatase, catalysing the incorporation of iron into PpIX thus forming cellular heme groups. This will lead to more efficient photodynamic action. Will involve performing MD simulations of docked inhibitor - receptor complexes, as well as quantum calcualtions of possible mechanisms and interactions. (iii) Investigate photochemical reactions and transmembrane diffusion of a series of potential photosensitizers in the tetrapyrrole, perylenequinone and furcoumarin families. This involves a mixture of MD simulations at atomistic and coarse-grained level, and quantum chemical studies (including TD-DFT of excited states) of explicit moelcules or complexes. (iv) Explore possible usage of cyclodextrins as drug carriers, for use in PDT. Will involve MD simulations as well as quantum chemical studies. (v) Investigate the interactions between mycotoxins (bleomycin and aflatoxins) with DNA and with biological membranes, and search for new possible derivatives thereof for use in combination treatments of cancer using electroporation and PDT. Will primarily be run at the MD level. (vi) Develop new non-steroid anti-inflammatory drugs with less phototoxic side effects. This involves a combination of quantum chemistry, excited state chemistry, molecular docking and molecular dynamics simulations of the new NSAIDs and of their interactions with COX-1 and COX-2.