Structure-based drug design: From nucleic acid to membrane protein targets

• Published in: Experimental and molecular pathology Vol. 86; no. 3; pp. 141 - 150
• Main Authors: Dailey, Magdalena M., Hait, Chayanendu, Holt, Patrick A., Maguire, Jon M., Meier, Jason B., Miller, M. Clarke, Petraccone, Luigi, Trent, John O.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-06-2009
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Computer Simulation; DNA; Drug Design; Drug discovery; Drug Discovery - methods; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - statistics & numerical data; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; G-protein coupled receptor; Humans; In Vitro Techniques; Macrophage Migration-Inhibitory Factors - antagonists & inhibitors; Macrophage Migration-Inhibitory Factors - chemistry; Membrane protein; Membrane Proteins - chemistry; Membrane Proteins - drug effects; Models, Molecular; Molecular Structure; Nucleic Acids - chemistry; Nucleic Acids - drug effects; Nucleolin; Phosphofructokinase-2 - antagonists & inhibitors; Phosphofructokinase-2 - chemistry; Phosphoproteins - chemistry; Phosphoproteins - drug effects; Quadruplex; Receptors, CXCR4 - chemistry; Receptors, CXCR4 - drug effects; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - drug effects; Telomerase - antagonists & inhibitors; Telomerase - chemistry; Telomere; User-Computer Interface; Virtual screening; Membrane protein; PFKFB3; ADME; Virtual screening; MIF; Quadruplex; Telomere; G-protein coupled receptor; EMSA; DNA; rmsd; GPCR; Drug discovery
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2009.01.011

The
in silico methods for drug discovery are becoming increasingly powerful and useful. That, in combination with increasing computer processor power, in our case using a novel distributed computing grid, has enabled us to greatly enhance our virtual screening efforts. Herein we review some of these efforts using both receptor and ligand-based virtual screening, with the goal of finding new anti-cancer agents. In particular, nucleic acids are a neglected set of targets, especially the different morphologies of duplex, triplex, and quadruplex DNA, many of which have increasing biological relevance. We also review examples of molecular modeling to understand receptors and using virtual screening against G-protein coupled receptor membrane proteins.