Free Resources to Assist Structure-Based Virtual Ligand Screening Experiments

Abstract

In today's research environment, a wealth of experimental/theoretical structural data is available and the number of therapeutically relevant macromolecular structures is growing rapidly. This, coupled with the huge number of small non-peptide potential drug candidates easily available (over 7 million compounds), highlight the need of using computer-aided techniques for the efficient identification and optimization of novel hit compounds. Virtual (or in silico) ligand screening based on the three-dimensional structure of macromolecular targets (SB-VLS) is firmly established as an important approach to identify chemical entities that have a high likelihood of binding to a target molecule to elicit desired biological responses. A myriad of free applications and services facilitating the drug discovery process have been posted on the Web. In this review, we cite over 350 URLs that are useful for SB-VLS projects and essentially free for academic groups. We attempt to provide links for in silico ADME/tox prediction tools, compound collections, some ligand-based methods, characterization/simulation of 3D targets and homology modeling tools, druggable pocket predictions, active site comparisons, analysis of macromolecular interfaces, protein docking tools to help identify binding pockets and protein-ligand docking/scoring methods. As such, we aim at providing both, methods pertaining to the field of Structural Bioinformatics (defined here as tools to study macromolecules) and methods pertaining to the field of Chemoinformatics (defined here as tools to make better decisions faster in the arena of drug/lead identification and optimization). We also report several recent success stories using these free computer methods. This review should help readers finding free computer tools useful for their projects. Overall, we are confident that these tools will facilitate rapid and cost-effective identification of new hit compounds. The URLs presented in this review will be updated regularly at www.vls3d.com in the coming months, "Links" section.

Using Open Source Computational Tools for Predicting Human Metabolic Stability and Additional Absorption, Distribution, Metabolism, Excretion, and Toxicity Properties

“…Several ADME/Tox methods had been proposed at least a decade ago, and the application or comparison of these programs has been extensively studied (Ekins et al, 2000b(Ekins et al, , 2001aEkins, 2007;Villoutreix et al, 2007;Lagorce et al, 2008). The challenge is not only that sizable drug discovery data (training sets) are lacking for model building but also that there has been no mechanism to bring together isolated training sets, especially the very large proprietary datasets from different companies.…”

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

“…2) [222]. Previous successful development of protein inhibitors using free virtual screening packages, mainly AutoDock and DOCK, have been reviewed by Bruno et al in their review [223]. Tanaji et al reviewed the development of 12 small molecules that have entered late clinical trials or final approved by FDA for therapeutic use as direct consequences of structure-based drug design [224].…”

Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

“…Ligand-based approaches include similarity searching, substructure, clustering, quantitative structure-activity relationships (QSAR), pharmacophore-, or three-dimensional shape matching techniques (Villoutreix et al, 2007). Several ligand-based methods, including similarity searching and QSAR, can roughly be divided into two-or three-dimensional approaches.…”