Virtual screening with AutoDock: theory and practice

Importance of the field: Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules. Areas covered in this review: We describe virtual screening methods that are available in the AutoDock suite of programs and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery. What the reader will gain: A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges. Take home message: Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening. © 2010 Informa UK Ltd

Identification of novel beta-secretase inhibitors through the inclusion of protein flexibility in virtual screening calculations

Alzheimer’s disease is a neurodegenerative disorder featuring both the aggregation of extraneuronal amyloid plaques and intraneuronal neurofibrillary tangles. The deposition of Aβ peptides in the brain plays a key role in the onset and progression of this disease, and β-secretase (BACE-1) is critical in this process. Thus, the inhibition of this enzyme is an attractive approach to anti-Alzheimer therapy. So far, the rational design of new BACE-1 inhibitors has been hampered by the intrinsic flexibility displayed by the enzyme which is not included in standard molecular modeling methods. Here, we incorporated protein flexibility into Virtual Screening (VS) in order to discover new BACE-1 inhibitors in two ways. First, we used an ensemble of static Xray BACE-1 structures representing the receptor flexibility in a VS of the NCI database. Also, the different conformations of BACE-1 were combined to generate a unified description of the protein motion. To do this, a set of map..

Structure-Based Virtual Screening and Biological Evaluation of Mycobacterium tuberculosis Adenosine 5 '-Phosphosulfate Reductase Inhibitors

Tuberculosis is among the world's deadliest infectious diseases. APS reductase catalyzes the first committed step in bacterial sulfate reduction and is a validated drug target against latent tuberculosis infection. We performed a virtual screening to identify APSR inhibitors. These inhibitors represent the first non-phosphate-based molecules to inhibit APSR. Common chemical features lay the foundation for the development of agents that could shorten the duration of chemotherapy by targeting the latent stage of TB infection. © 2008 American Chemical Society

Visualization of macromolecular structures

Structural biology is rapidly accumulating a wealth of detailed information about protein function, binding sites, RNA, large assemblies and molecular motions. These data are increasingly of interest to a broader community of life scientists, not just structural experts. Visualization is a primary means for accessing and using these data, yet visualization is also a stumbling block that prevents many life scientists from benefiting from three-dimensional structural data. In this review, we focus on key biological questions where visualizing three-dimensional structures can provide insight and describe available methods and tools