Prof. W. Andrzej Sokalski, Wroclaw University of Science and Technology

data wydarzenia: 17 maja 2019

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

 

Abstract:

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 [1],  pteridine reductase [2], menin [3 and phosphodiesterase [4] 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 [5],  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 [6]. These problems  could be resolved  by  employing  differential transition state stabilization DTSS  approach [7], which  indicates clearly  the  key role  of  multipolar electrostatic term [8], which has  been  recently confirmed also  by experiment [9].  Wherever electrostatic contribution is dominant it is possible to derive general characteristics of optimal molecular environment in the form of catalytic field [7] 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 [10],  verification of  enzyme reaction mechanisms and  detecting  catalytic activity of  hydrogen  bond  chains  in enzymes.

 

 

References :

  1. W. Jedwabny et al., J.Phys.Chem. B, 118, 14727 (2014).
  2. W. Jedwabny at al., J. Comp.Aided Mol.Design, 31, 715 (2017).
  3. W. Jedwabny et al., MedChemComm, 8,2216(2017).
  4. W. Jedwabny et al., J.Mol.Model.  25,29 (2019)
  5. S. D. Khare et al., Nature Chem. Biol.,8,294 (2012).
  6. C. H. Arnaud, Chem. Eng. News, 91, 26 (2013). Ibid, 92, 36 (2014).
  7. B. Szefczyk et al., J.Am. Chem. Soc.126,16148 (2004).
  8. W. Beker et al.,   J. Chem. Theor. Comp., 13,945( 2017).
  9. S.D. Fried, S. Bagchi, S.G. Boxer, Science, 346, 1510 (2014).
  10. M. Chojnacka et al., J.Mol.Model. 24, 28 (2018)