PubChem is a chemical information repository, consisting of three primary databases: Substance, Compound, and BioAssay. When individual data contributors submit substance descriptions to the unique structures are extracted stored into Compound through an automated process called structure standardization. The present study describes standardization approaches analyzes them for their success rates, reasons that cause be rejected, modifications applied during process. Furthermore, compared...

De novo design of drug-like compounds with a desired pharmacological activity profile has become feasible through innovative computer algorithms. Fragment-based and simulated chemical reactions allow for the rapid generation candidate as blueprints organic synthesis.We used combination complementary virtual-screening tools analysis de designed that were generated aim to inhibit inactive polo-like kinase 1 (Plk1), target development cancer therapeutics. A homology model state Plk1 was...

Abstract An updated version of the SMILIB software tool for rapid combinatorial library enumeration was developed. SmiLib v2.0 offers possibility to construct very large libraries using flexible and portable SMILES format. Libraries were created at rates approximately 8 700 000 molecules per minute. Combinatorial building blocks are attached scaffolds by means linkers rather than concatenate them directly. This allows creation customized different sizes chemical nature. New features are:...

Developing structure-activity relationships (SARs) of molecules is an important approach in facilitating hit exploration the early stage drug discovery. Although information on millions compounds and their bioactivities freely available to public, it very challenging infer a meaningful novel SAR from that information.Research discussed present paper employed bioactivity-centered clustering group 843,845 non-inactive stored PubChem according both structural similarity bioactivity similarity,...

Abstract We present a ligand‐based virtual screening technique (PhAST) for rapid hit and lead structure searching in large compound databases. Molecules are represented as strings encoding the distribution of pharmacophoric features on molecular graph. In contrast to other text‐based methods using SMILES strings, we introduce new form text representation that describes pharmacophore molecules. This string opens opportunity revealing functional similarity between molecules by sequence...

Atom environments and fragments find wide-spread use in chemical information cheminformatics. They are the basis of prediction models, an integral part similarity searching, employed structure search techniques. Most these methods were developed evaluated on relatively small sets structures available at time. An analysis fragment distributions representative most known was published 1970s using Chemical Abstracts Service data system. More recently, advances automated synthesis chemicals...

Abstract Modulation of protein–protein interactions (PPI) has emerged as a new concept in rational drug design. Here, we present computational protocol for identifying potential PPI inhibitors. Relevant regions interfaces (epitopes) are predicted three‐dimensional protein models and serve queries virtual compound screening. We screening that incorporates two different pharmacophore models. One model is based on the mathematical autocorrelation vectors other utilizes fuzzy labeled graphs. In...

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Previously, (Hähnke et al., J Comput Chem 2009, 30, 761) we presented the Pharmacophore Alignment Search Tool (PhAST), a ligand-based virtual screening technique representing molecules as strings coding pharmacophoric features and comparing them by global pairwise sequence alignment. To guarantee unambiguity during reduction of two-dimensional molecular graphs to one-dimensional strings, PhAST employs graph canonization step. Here, present results comparison 11 different algorithms for with...

Antimicrobial activity of trimethoprim/sulfamethoxazole (SXT) against Staphylococcus aureus (S. aureus) is antagonized by thymidine, which abundant in infected or inflamed human tissue. To restore the antimicrobial SXT presence we screened for small-molecule inhibitors S. thymidine kinase with non-nucleoside scaffolds. We present successful application an adaptive virtual screening protocol novel antibiotics using a combination ligand- and structure-based approaches. Two consecutive rounds...

Abstract The text‐based similarity searching method Pharmacophore Alignment Search Tool is grounded on pairwise comparisons of potential pharmacophoric points between a query and screening compounds. underlying scoring matrix critical importance for successful virtual hit retrieval from large compound libraries. Here, we compare three conceptually different computational methods systematic deduction matrices: assignment‐based, alignment‐based, stochastic optimization. All resulted in...

Background: Chemical similarity searching allows the retrieval of preferred screening molecules from a compound database. Candidates are ranked according to their reference (query). Assessing statistical significance chemical scores helps prioritizing significant hits, and identifying cases where database does not contain any promising compounds. Method: Our text-based measure, Pharmacophore Alignment Search Tool (PhAST), employs pair-wise sequence alignment. We adapted concept E-values as...

We present an integrated approach to identify and optimize a novel class of γ-secretase modulators (GSMs) with unique pharmacological profile. Our strategy included (i) virtual screening through application recently developed protocol (PhAST), (ii) synthetic chemistry discover structure-activity relationships, (iii) detailed in vitro characterization. GSMs are promising agents for treatment or prevention Alzheimer's disease. They modulate the product spectrum (i.e., amyloid-β (Aβ) peptides...

Abstract Previously (Hähnke et al., J Comput Chem 2010, 31, 2810) we introduced the concept of nonlinear dimensionality reduction for canonization two‐dimensional layouts molecular graphs as foundation text‐based similarity searching using our Pharmacophore Alignment Search Tool (PhAST), a ligand‐based virtual screening method. Here apply these methods to three‐dimensional conformations and investigate impact additional degrees freedom on performance assess differences in ranking behavior....

Abstract Previously, we proposed a ligand‐based virtual screening technique (PhAST) based on global alignment of linearized interaction patterns. Here, applied techniques developed for similarity assessment in local sequence alignments to our method resulting p ‐values chemical similarity. We compared two sampling strategies, simple strategy and Markov Chain Monte Carlo (MCMC) method, investigated the sampled distributions Gaussian, Gumbel, modified Gamma distributions. The Gumbel...

PubChem is an open repository for molecular structures, their properties and biological activities [1]. The number of deposited structures has been steadily increasing since its creation in 2004. Today, it contains more than 92 million substances (PubChem Substance) with 32 unique small molecules Compound). Consequently, visual inspection every structure correction errors by hand to detect equivalencies ensure data quality are not feasible. Efficient reliable automated methods...