A molecular-modeling toolbox aimed at bridging the gap between medicinal chemistry and computational sciences.
In the current era of high-throughput drug discovery and development, molecular modeling has become an indispensable tool for identifying, optimizing and prioritizing small-molecule drug candidates. The required background in computational chemistry and the knowledge of how to handle the complex underlying protocols, however, might keep medicinal chemists from routinely using in silico technologies. Our objective is to encourage those researchers to exploit existing modeling technologies more frequently through easy-to-use graphical user interfaces. In this account, we present two innovative tools (which we are prepared to share with academic institutions) facilitating computational tasks commonly utilized in drug discovery and development: (1) the VirtualDesignLab estimates the binding affinity of small molecules by simulating and quantifying their binding to the three-dimensional structure of a target protein; and (2) the MD Client launches molecular dynamics simulations aimed at exploring the  time-dependent stability of ligand-protein complexes and provides residue-based interaction energies. This allows medicinal chemists to identify sites of potential improvement in their candidate molecule. As a case study, we present the application of our tools towards the design of novel antagonists for the FimH adhesin.
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. angelo.vedani@unibas.ch.
Sameh
S
Eid
Adam
A
Zalewski
Martin
M
Smieško
Beat
B
Ernst
Angelo
A
Vedani
D018830:Adhesins, Escherichia coli / Q000737:chemistry / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D036781:Fimbriae Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship
D018830:Adhesins, Escherichia coli; D011506:Proteins; D054852:Small Molecule Libraries; C058769:fimH protein, E coli; D036781:Fimbriae Proteins