Dataset Information

Molpher: a software framework for systematic chemical space exploration.

ABSTRACT: BACKGROUND:Chemical space is virtual space occupied by all chemically meaningful organic compounds. It is an important concept in contemporary chemoinformatics research, and its systematic exploration is vital to the discovery of either novel drugs or new tools for chemical biology. RESULTS:In this paper, we describe Molpher, an open-source framework for the systematic exploration of chemical space. Through a process we term 'molecular morphing', Molpher produces a path of structurally-related compounds. This path is generated by the iterative application of so-called 'morphing operators' that represent simple structural changes, such as the addition or removal of an atom or a bond. Molpher incorporates an optimized parallel exploration algorithm, compound logging and a two-dimensional visualization of the exploration process. Its feature set can be easily extended by implementing additional morphing operators, chemical fingerprints, similarity measures and visualization methods. Molpher not only offers an intuitive graphical user interface, but also can be run in batch mode. This enables users to easily incorporate molecular morphing into their existing drug discovery pipelines. CONCLUSIONS:Molpher is an open-source software framework for the design of virtual chemical libraries focused on a particular mechanistic class of compounds. These libraries, represented by a morphing path and its surroundings, provide valuable starting data for future in silico and in vitro experiments. Molpher is highly extensible and can be easily incorporated into any existing computational drug design pipeline.

SUBMITTER: Hoksza D

PROVIDER: S-EPMC3998053 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molpher: a software framework for systematic chemical space exploration.

Hoksza David D Skoda Petr P Voršilák Milan M Svozil Daniel D

Journal of cheminformatics 20140321 1

<h4>Background</h4>Chemical space is virtual space occupied by all chemically meaningful organic compounds. It is an important concept in contemporary chemoinformatics research, and its systematic exploration is vital to the discovery of either novel drugs or new tools for chemical biology.<h4>Results</h4>In this paper, we describe Molpher, an open-source framework for the systematic exploration of chemical space. Through a process we term 'molecular morphing', Molpher produces a path of structu ...[more]

PMID: 24655571

Similar Datasets

Project description:Tuberculosis (TB), entrained by Mycobacterium tuberculosis, continues to be an enfeebling disease, killing nearly 1.5 million people in 2019, with 2 billion people worldwide affected by latent TB. The multidrug-resistant and totally drug-resistant emerging strains further exacerbate the TB infection. The cell wall of bacteria provides critical virulence components such as cell surface proteins, regulators, signal transduction proteins, and toxins. The cell wall biosynthesis pathway of Mycobacterium tuberculosis is exhaustively studied to discover novel drug targets. Decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1) is an important enzyme involved in the arabinogalactan biosynthetic pathway of Mycobacterium tuberculosis cell wall and is essential for both latent and persistent bacterial infection. We analyzed all known ∼1300 DprE1 inhibitors to gain deep insights into the chemogenomic space of DprE1-ligand complexes. Physicochemical descriptors of the DprE1 inhibitors showed a marked lipophilic character forming a cluster distinct from the existing TB drugs, as revealed by the principal component analysis. Similarity analysis using Murcko scaffolds and rubber band scaling revealed scarce representation of the chemical space. Further, Murcko scaffold analysis uncovered favorable and unfavorable scaffolds, where benzo and pyridine-based core scaffolds exhibit the highest biological activity, as evidenced by their MIC and IC50 values. Automatic SAR and R-group decomposition analysis resulted in the identification of substructures responsible for the inhibitory activity of the DprE1 enzyme. Further, with activity cliff analysis, we observed prominent discontinuity in the SAR of DprE1 inhibitors, where even simple structural modification in the chemical scaffold resulted in significant potency difference, presumably due to the binding orientation and interaction in the active site. Thiophene, 6-membered aromatic rings, and unsubstituted benzene ring-based toxicophores were identified in the DprE1 chemical space using an artificial intelligence approach based on inductive logic programming. This paper, hence, ushers in new insights for the design and development of potent covalent and non-covalent DprE1 inhibitors and guides hit and lead optimization for the development of non-hazardous small molecule therapeutics for Mycobacterium tuberculosis.

Project description:BACKGROUND:Effective implementation of evidence-based practices (EBPs) remains a significant challenge. Numerous existing models and frameworks identify key factors and processes to facilitate implementation. However, there is a need to better understand how individual models and frameworks are applied in research projects, how they can support the implementation process, and how they might advance implementation science. This systematic review examines and describes the research application of a widely used implementation framework, the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. METHODS:A systematic literature review was performed to identify and evaluate the use of the EPIS framework in implementation efforts. Citation searches in PubMed, Scopus, PsycINFO, ERIC, Web of Science, Social Sciences Index, and Google Scholar databases were undertaken. Data extraction included the objective, language, country, setting, sector, EBP, study design, methodology, level(s) of data collection, unit(s) of analysis, use of EPIS (i.e., purpose), implementation factors and processes, EPIS stages, implementation strategy, implementation outcomes, and overall depth of EPIS use (rated on a 1-5 scale). RESULTS:In total, 762 full-text articles were screened by four reviewers, resulting in inclusion of 67 articles, representing 49 unique research projects. All included projects were conducted in public sector settings. The majority of projects (73%) investigated the implementation of a specific EBP. The majority of projects (90%) examined inner context factors, 57% examined outer context factors, 37% examined innovation factors, and 31% bridging factors (i.e., factors that cross or link the outer system and inner organizational context). On average, projects measured EPIS factors across two of the EPIS phases (M?=?2.02), with the most frequent phase being Implementation (73%). On average, the overall depth of EPIS inclusion was moderate (2.8 out of 5). CONCLUSION:This systematic review enumerated multiple settings and ways the EPIS framework has been applied in implementation research projects, and summarized promising characteristics and strengths of the framework, illustrated with examples. Recommendations for future use include more precise operationalization of factors, increased depth and breadth of application, development of aligned measures, and broadening of user networks. Additional resources supporting the operationalization of EPIS are available.

Dataset Information

Molpher: a software framework for systematic chemical space exploration.

Publications

Molpher: a software framework for systematic chemical space exploration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure