WebChem Viewer: a tool for the easy dissemination of chemical and structural data sets.

BackgroundSharing sets of chemical data (e.g., chemical properties, docking scores, etc.) among collaborators with diverse skill sets is a common task in computer-aided drug design and medicinal chemistry. The ability to associate this data with images of the relevant molecular structures greatly facilitates scientific communication. There is a need for a simple, free, open-source program that can automatically export aggregated reports of entire chemical data sets to files viewable on any computer, regardless of the operating system and without requiring the installation of additional software.ResultsWe here present a program called WebChem Viewer that automatically generates these types of highly portable reports. Furthermore, in designing WebChem Viewer we have also created a useful online web application for remotely generating molecular structures from SMILES strings. We encourage the direct use of this online application as well as its incorporation into other software packages.ConclusionsWith these features, WebChem Viewer enables interdisciplinary collaborations that require the sharing and visualization of small molecule structures and associated sets of heterogeneous chemical data. The program is released under the FreeBSD license and can be downloaded from http://nbcr.ucsd.edu/WebChemViewer. The associated web application (called "Smiley2png 1.0") can be accessed through freely available web services provided by the National Biomedical Computation Resource at http://nbcr.ucsd.edu

Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors.

Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc-binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand

Scoria: a Python module for manipulating 3D molecular data

Third-party packages have transformed the Python programming language into a powerful computational-biology tool. Package installation is easy for experienced users, but novices sometimes struggle with dependencies and compilers. This presents a barrier that can hinder the otherwise broad adoption of new tools. We present Scoria, a Python package for manipulating three-dimensional molecular data. Unlike similar packages, Scoria requires no dependencies, compilation, or system-wide installation. One can incorporate the Scoria source code directly into their own programs. But Scoria is not designed to compete with other similar packages. Rather, it complements them. Our package leverages others (e.g. NumPy, SciPy), if present, to speed and extend its own functionality. To show its utility, we use Scoria to analyze a molecular dynamics trajectory. Our FootPrint script colors the atoms of one chain by the frequency of their contacts with a second chain. We are hopeful that Scoria will be a useful tool for the computational-biology community. A copy is available for download free of charge (Apache License 2.0) at http://durrantlab.com/scoria/

From Byte to Bench to Bedside: Molecular Dynamics Simulations and Drug Discovery

Molecular dynamics (MD) simulations and computer-aided drug design (CADD) have advanced substantially over the past two decades, thanks to continuous computer hardware and software improvements. Given these advancements, MD simulations are poised to become even more powerful tools for investigating the dynamic interactions between potential small-molecule drugs and their target proteins, with significant implications for pharmacological research.Comment: 15 pages including references, 0 figure

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

Computational techniques such as structure-based virtual screening require carefully prepared 3D models of potential small-molecule ligands. Though powerful, existing commercial programs for virtual-library preparation have restrictive and/or expensive licenses. Freely available alternatives, though often effective, do not fully account for all possible ionization, tautomeric, and ring-conformational variants. We here present Gypsum-DL, a free, robust open-source program that addresses these challenges. As input, Gypsum-DL accepts virtual compound libraries in SMILES or flat SDF formats. For each molecule in the virtual library, it enumerates appropriate ionization, tautomeric, chiral, cis/trans isomeric, and ring-conformational forms. As output, Gypsum-DL produces an SDF file containing each molecular form, with 3D coordinates assigned. To demonstrate its utility, we processed 1558 molecules taken from the NCI Diversity Set VI and 56,608 molecules taken from a Distributed Drug Discovery (D3) combinatorial virtual library. We also used 4463 high-quality protein-ligand complexes from the PDBBind database to show that Gypsum-DL processing can improve virtual-screening pose prediction. Gypsum-DL is available free of charge under the terms of the Apache License, Version 2.0

Novel cruzain inhibitors for the treatment of Chagas' disease.

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease

Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design.

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads

Towards the development of novel Trypanosoma brucei RNA editing ligase 1 inhibitors

Abstract Background Trypanosoma brucei (T. brucei) is an infectious agent for which drug development has been largely neglected. We here use a recently developed computer program called AutoGrow to add interacting molecular fragments to S5, a known inhibitor of the validated T. brucei drug target RNA editing ligase 1, in order to improve its predicted binding affinity. Results The proposed binding modes of the resulting compounds mimic that of ATP, the native substrate, and provide insights into novel protein-ligand interactions that may be exploited in future drug-discovery projects. Conclusions We are hopeful that these new predicted inhibitors will aid medicinal chemists in developing novel therapeutics to fight human African trypanosomiasis

Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

Virtual molecular catalogs have limited utility if member compounds are (i) difficult to synthesize or (ii) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays. The results provide insight into the broad range of drug-target classes amenable to inhibition and/or agonism by D3-accessible molecules. To encourage computer-aided drug discovery centered on these compounds, a publicly available virtual database of D3 molecules prepared for use with popular computer docking programs is also presented