Advanced drug design strategies
Currently, drug design based on the paradigm of combining the fitting of drug molecule structures to target binding sites with high throughput screening and other data based methods has reached the point of diminishing returns. This phenomenon is known as “Erooms law”; the number of new approved drugs remains constant as the resources spent on drug development increase exponentially. Getting out of this rut requires thinking out of the box: a wide range of novel strategies based on a broader paradigm. We have applied our combined experimental-computational toolkit to a variety of such novel approaches. This includes the study of more subtle mechanisms for drug-protein interactions than simply matching the form of the drug molecule to a specific active site and using computational modeling to assist the development of immunotherapy vectors and cell penetrating peptides. Links to our publications in this area are below.
Publications in this area:
Marco G. Casteleijn, Petteri Parkkila, Tapani Viitala and Artturi Koivuniemi: Interaction of lecithin-cholesterol acyltransferase with lipid surfaces and apolipoprotein A-I derived peptides. J. Lipid Res. in press (2018).
Aniket Magarkar, Petteri Parkkila, Tapani Viitala, Tatu Lajunen, Edouard Mobarak, Giuseppe Licari, Oana Cramariuc, Eric Vauthey, Tomasz Róg and Alex Bunker: Membrane bound COMT isoform is an interfacial enzyme: general mechanism and new drug design paradigm. Chem. Commun. in press (2018).
Silvia Hilt, Tatu Rojalin, Tapani Viitala, Artturi Koivuniemi, Alex Bunker, Sebastian Wachsmann-Hogiu, Tamás Kálai, Kálmán Hideg, Marjo Yliperttula and John C. Voss: Oligomerization Alters Binding Affinity between Amyloid Beta and a Modulator of Peptide Aggregation. J. Phys. Chem. C. 121(43), pp. 23974–23987
C. Capasso, M. Hirvinen, M. Garofalo, D. Romaniuk, L. Kuryk, T. Sarvela, Vitale A., M. Antopolsky, A. Magarkar, T. Viitala, A. Bunker, M. Yliperttula, A. Urtti and V. Cerullo: Oncolytic adenoviruses coated with MHC-I tumor epitopes increase the anti-tumor immunity and efficacy against melanoma. Oncoimmunology 5(4), e1105429 (2016).
Adam Orłowski, Alex Bunker, Marta Pasenkiewicz-Gierula, Ilpo Vattulainen, P. T. Männistö and Tomasz Róg: Strong preferences of dopamine and L-dopa towards lipid headgroup: importance of phosphatidylserine and its implication for neurotransmitter metabolism. J. Neurochem. 122, pp. 612–690 (2012).
A. Subrizi, E. Tuominen, A. Bunker, T. Róg, M. Antopolsky, and A. Urtti: TAT(48-60) Peptide amino acid sequence is not unique in its cell penetrating properties and cell-surface glycosaminoglycans inhibit its cellular uptake. J. Control. Release 158(2), pp. 277−285 (2012).
Karol Kaszuba, Tomasz Róg, Reinis Danne, Peter Canning, Vilmos Fülöp, Tünde Juhász, Zoltán Szeltner, J-F. St. Pierre, Arturo Garcıa-Horsman, P. T. Mannisto, Mikko Karttunen, Jyrki Hokkanen and Alex Bunker: Molecular dynamics, crystallography and mutagenesis studies on the substrate gating mechanism of prolyl oligopeptidase. Biochimie 94(6), pp. 1398-1411 (2012).
Adam Orłowski, J-F. St-Pierre, Aniket Magarkar, Alex Bunker, Marta Pasenkiewicz-Gierula, Mikko Karttunen, Ilpo Vattulainen, and Tomasz Róg: Properties of the membrane binding component of Catechol-O-methyltransferase revealed by atomistic molecular dynamics simulations. J. Phys. Chem. B 115(46), pp. 13541−13550 (2011).
Jean-Francois St. Pierre, Mikko Karttunen, Alex Bunker, Tomasz Róg and Normand Mousseau: Use of Umbrella Sampling to Calculate the Entrance/Exit Pathway for Z-Pro-Prolinal Inhibitor in Prolyl Oligopeptidase. J. Chem. Theory and Comput. 7(6), pp. 1583−1594 (2011).
Karol Kaszuba, Tomasz Róg, Jean-Francois St. Pierre, Pekka T. Männistö, Mikko Karttunen, and Alex Bunker: Molecular Dynamics Study of Prolyl Oligopeptidase with Inhibitor in Binding Cavity. SAR and QSAR in Env. Res. 20(7-8), pp. 595−609 (2009).