Constructing high-quality libraries of molecular building blocks is essential for successful fragment-based drug discovery. In this communication, we describe eMolFrag, a new open-source software to decompose organic compounds into nonredundant fragments retaining molecular connectivity information. Given a collection of molecules, eMolFrag generates a set of unique fragments comprising larger moieties, bricks, and smaller linkers connecting bricks. These building blocks can subsequently be used to construct virtual screening libraries for targeted drug discovery. The robustness and computational performance of eMolFrag is assessed against the Directory of Useful Decoys, Enhanced database conducted in serial and parallel modes with up to 16 computing cores. Further, the application of eMolFrag in de novo drug design is illustrated using the adenosine receptor. eMolFrag is implemented in Python, and it is available as stand-alone software and a web server at and .
BackgroundDue to exorbitant costs of high-throughput screening, many drug discovery projects commonly employ inexpensive virtual screening to support experimental efforts. However, the vast majority of compounds in widely used screening libraries, such as the ZINC database, will have a very low probability to exhibit the desired bioactivity for a given protein. Although combinatorial chemistry methods can be used to augment existing compound libraries with novel drug-like compounds, the broad chemical space is often too large to be explored. Consequently, the trend in library design has shifted to produce screening collections specifically tailored to modulate the function of a particular target or a protein family. MethodsAssuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. On this account, we developed eSynth, an exhaustive graph-based search algorithm to computationally synthesize new compounds by reconnecting these building blocks following their connectivity patterns.ResultsWe conducted a series of benchmarking calculations against the Directory of Useful Decoys, Enhanced database. First, in a self-benchmarking test, the correctness of the algorithm is validated with the objective to recover a molecule from its building blocks. Encouragingly, eSynth can efficiently rebuild more than 80 % of active molecules from their fragment components. Next, the capability to discover novel scaffolds is assessed in a cross-benchmarking test, where eSynth successfully reconstructed 40 % of the target molecules using fragments extracted from chemically distinct compounds. Despite an enormous chemical space to be explored, eSynth is computationally efficient; half of the molecules are rebuilt in less than a second, whereas 90 % take only about a minute to be generated.ConclusionseSynth can successfully reconstruct chemically feasible molecules from molecular fragments. Furthermore, in a procedure mimicking the real application, where one expects to discover novel compounds based on a small set of already developed bioactives, eSynth is capable of generating diverse collections of molecules with the desired activity profiles. Thus, we are very optimistic that our effort will contribute to targeted drug discovery. eSynth is freely available to the academic community at www.brylinski.org/content/molecular-synthesis.Graphical abstractAssuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. Here, we developed eSynth, an automated method to synthesize new compounds by reconnecting these building blocks following the connectivity patterns via an exhaustive graph-based search algorithm. eSynth opens up a possibility to rapidly construct virtual screening libraries for targeted drug discovery
This paper presents a semi-automated methodology for generating geometric proof problems of the kind found in a high-school curriculum. We formalize the notion of a geometry proof problem and describe an algorithm for generating such problems over a user-provided figure. Our experimental results indicate that our problem generation algorithm can effectively generate proof problems in elementary geometry. On a corpus of 110 figures taken from popular geometry textbooks, our system generated an average of about 443 problems per figure in an average time of 4.7 seconds per figure.
UML sequence diagrams are visual representations of object interactions in a system and can provide valuable information for program comprehension, debugging, maintenance, and software archeology. Sequence diagrams generated from legacy code are independent of existing documentation that may have eroded. We present a framework for static generation of UML sequence diagrams from object-oriented source code. The framework provides a query refinement system to guide the user to interesting interactions in the source code. Our technique involves constructing a hypergraph representation of the source code, traversing the hypergraph with respect to a user-defined query, and generating the corresponding set of sequence diagrams. We implemented our framework as a tool, StaticGen (supporting software: StaticGen ), analyzing a corpus of 30 Android applications. We provide experimental results demonstrating the efficacy of our technique (originally appeared in the Proceedings of Fundamental Approaches to Software Engineering—20th International Conference, FASE 2017, Held as Part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2017, Uppsala, Sweden, April 22–29, 2017).
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