Abstract

The exploration of large-scale active site motions, and their affect on ligand discovery and optimization, is currently one of the most under-investigated areas in structure-based drug design. The proposed """"""""SMD- relaxed complex"""""""" method addresses the challenge of increasing the receptor conformational space in a computationally efficient manner. Steered molecular dynamics simulations will be employed to remove a bound ligand from the receptor's active site, thereby accelerating the sampling of the receptor's conformational space. For receptors with deeply buried ligands or flexible loops, this technique could add significant insight into the prediction and evaluation of large domain motions and the effects of active site flexibility on inhibitor binding. The resulting receptor conformations will be ordered with the QR factorization algorithm, and the non-redundant, representative set of structures will be used to develop novel pharmacophore models and as input to the relaxed complex drug design protocol. The success of this new approach will be demonstrated on an essential RNA editing enzyme found in the trypanosomatid pathogens, which are responsible for several devastating tropical diseases. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM077729-02
Application #
7290299
Study Section
Special Emphasis Panel (ZRG1-F04B-P (20))
Program Officer
Flicker, Paula F
Project Start
2006-09-01
Project End
2009-02-28
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$48,796
Indirect Cost

  Institution

Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Malmstrom, Robert D; Kornev, Alexandr P; Taylor, Susan S et al. (2015) Allostery through the computational microscope: cAMP activation of a canonical signalling domain. Nat Commun 6:7588
Amaro, Rommie E; Li, Wilfred W (2010) Emerging methods for ensemble-based virtual screening. Curr Top Med Chem 10:3-13
Sung, Jeffrey C; Van Wynsberghe, Adam W; Amaro, Rommie E et al. (2010) Role of secondary sialic acid binding sites in influenza N1 neuraminidase. J Am Chem Soc 132:2883-5
Durrant, Jacob D; Hall, Laurence; Swift, Robert V et al. (2010) Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. PLoS Negl Trop Dis 4:e803
Durrant, Jacob D; Amaro, Rommie E; Xie, Lei et al. (2010) A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology. PLoS Comput Biol 6:e1000648
Newhouse, E Irene; Xu, Dong; Markwick, Phineus R L et al. (2009) Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective. J Am Chem Soc 131:17430-42
Swift, Robert V; Durrant, Jacob; Amaro, Rommie E et al. (2009) Toward understanding the conformational dynamics of RNA ligation. Biochemistry 48:709-19
Durrant, Jacob D; Amaro, Rommie E; McCammon, J Andrew (2009) AutoGrow: a novel algorithm for protein inhibitor design. Chem Biol Drug Des 73:168-78
Xu, Dong; Newhouse, E Irene; Amaro, Rommie E et al. (2009) Distinct glycan topology for avian and human sialopentasaccharide receptor analogues upon binding different hemagglutinins: a molecular dynamics perspective. J Mol Biol 387:465-91
Amaro, Rommie E; Cheng, Xiaolin; Ivanov, Ivaylo et al. (2009) Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations. J Am Chem Soc 131:4702-9

Showing the most recent 10 out of 17 publications