The Centre of New Technologies invites to a seminar by
Prof. Andrzej Sokalski
Advanced Materials Engineering and Modelling Group
Wrocław University of Science and Technology
NONEMPIRICAL METHODS AIDING DRUG AND BIOCATALYST DESIGN
May 17th, 2019 at 12 p.m.
Venue: Centre of New Technologies, Banacha 2C,
Lecture Hall 0142 (Ground floor)
Host: Prof. D. Plewczyński
Currently used empirical scoring techniques used in de-novo drug design are still unreliable, whereas alternative computational methods are too costly or too sensitive to docking errors. Our results obtained for fatty acid amide hydrolase , pteridine reductase , menin [3 and phosphodiesterase  inhibitors indicate that the multipole electrostatic and dispersion model (MED) could be applied to obtain low cost nonempirical ranking of inhibitory activity, in particular when inhibitor solvation effects are not too different.
Recent progress in theoretical biocatalyst design has been stalled after some initial successes , because theozymes display rather low catalytic activity and conventional models are not yet capable to explain the role of additional mutations in second coordination sphere, introduced by directed evolution experiments . These problems could be resolved by employing differential transition state stabilization DTSS approach , which indicates clearly the key role of multipolar electrostatic term , which has been recently confirmed also by experiment . Wherever electrostatic contribution is dominant it is possible to derive general characteristics of optimal molecular environment in the form of catalytic field  enabling catalyst inverse design. Combination of information contained in catalytic field with scanning of all possible sidechain conformations using database of atomic multipoles for amino acid rotamers allows to consider all possible dynamic catalytic effects in the timescale out of reach for conventional methods based on molecular dynamics. Such methodology has been recently applied to explain catalytic activity of multiple mutants in the second coordination sphere of Kemp eliminase obtained by directed evolution. Some other applications of catalytic fields will be discussed including substrate assisted catalysis , verification of enzyme reaction mechanisms and detecting catalytic activity of hydrogen bond chains in enzymes.
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