Title: BIO-MAT Joint Seminar Announcement
Speaker: Deniz Sezer
Date/Time: November 25, Wednesday, 12:40 - 13:30
Place: FENS G035
Abstract: A recent study investigating the acid/base properties of small molecule drugs and compounds that can be purchased to screen their potential use as drugs has reported a striking difference between the two groups of molecules . Among the 3766 analyzed drugs, 27% were found to be aliphatic amines and 20% to be carboxylic acids . In contrast, only 3.4% and 2.4% of the examined screening compounds were found to contain aliphatic amine and carboxylic acid, respectively . Being based on the analysis of databases containing human approved drugs and screening compounds, this finding does not reveal the physicochemical factors responsible for the preference of these two chemical groups among the actual drugs. I hypothesize that the aliphatic amine and carboxylic acid moieties are important for the passive permeation of the small molecule drugs through the lipid component of the cell membrane. In this talk, I will introduce the computational strategy that we pursue to test this hypothesis. We employ atomistic molecular dynamics (MD) simulations to model the permeation of the drug dyclonine, which contains an aliphatic amine, through a lipid bilayer composed of DPPC lipids. The free energy profiles calculated from the MD simulations are subsequently used to model the protonation/deprotonation kinetics of dyclonine. Our analysis provides a mechanistic explanation for the prevalence of aliphatic amines and carboxylic acids among the drugs. Understanding the physicochemical factors controlling the passive permeation of aliphatic amines and carboxylic acids across the lipid bilayer may lead to the design of drug pairs that “help” each other to cross the cell membrane. This may facilitate the prediction of synergistic drug pairs, whose joint efficacy is larger than the sum of their separate efficacies . REFERENCES
 D. T. Manallack, R. J. Prankerd, G. C. Nassta, O. Ursu, T. I. Oprea, D. K. Chalmers, “A Chemogenomic Analysis of Ionization Constants – Implications for Drug Discovery,” ChemMedChem 2013, 8: 242-255.  M. Çokol, H. N. Chua, M. Taşan, B. Mutlu, Z. Weinstein, Y. Suzuki, M. E. Ercan, M. Costanzo, A. Baryshnikova, G. Giaever, C. Nislow, C. L. Myers, B. J. Andrews, C. Boone, F. P. Roth, “Systematic Exploration of Synergistic Drug Pairs,” Molecular Systems Biology 2011, 7, art. 544:1-9.
Biography: Deniz Sezer is a faculty member in the Faculty of Engineering and Natural Sciences at Sabancı University, where he teaches courses on Biophysics and Structural Biology. His computational research focuses on modeling the dynamics of (bio)molecules with the purpose of predicting various aspects of their magnetic resonance spectra. Deniz studied Electrical Engineering and Physics at Boğaziçi University, graduating in 1998. He obtained his Master’s degree in Physics from the same university in 2000. Between 2000 and 2008 he was a graduate student in the Physics department at Cornell University. During this period he worked successively at the following departments (institutions): Physics (Cornell University), Physiology and Biophysics (Graduate School of Medical Sciences of Cornell University), and Biochemistry and Molecular Biology (The University of Chicago). His PhD research was conducted in the group of Prof. Benoit Roux, who is mostly known for his computational work on potassium channels. From early 2008 until the end of 2009 Deniz was a postdoctoral researcher in the Institute of Physical and Theoretical Chemistry at the University of Frankfurt. There he worked in the group of Prof. Thomas Prisner, who pushes the limits of electron spin resonance (ESR) spectroscopy by developing new methodologies for the spectroscopic characterization of biological macromolecules.