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  • Pharmit: Interactive Exploration of Chemical Space

    Abstract

    Pharmit (http://pharmit.csb.pitt.edu) provides an online, interactive environment for the virtual screening of large compound databases using pharmacophores, molecular shape, and energy minimization. Users can import, create, and edit virtual screening queries in an interactive browser-based interface. Queries are specified in terms of a pharmacophore, a spatial arrangement of the essential features of an interaction, and molecular shape. Search results can be further ranked and filtered using energy minimization. In addition to a number of pre-built databases of popular compound libraries, users may submit their own compound libraries for screening. Pharmit uses state-of-the-art sub-linear algorithms to provide interactive screening of millions of compounds. Queries typically take a few seconds to a few minutes depending on their complexity. This allows users to iteratively refine their search during a single session. The easy access to large chemical datasets provided by Pharmit simplifies and accelerates structure-based drug design. Pharmit is available under a dual BSD/GPL open-source license.

    Introduction

    There are a multitude of software packages and web services that assist in computer aided drug design (Villoutreix 2013), but a relative paucity of web services that support structure-based virtual screening. Those that exist, such as DockBlaster (Irwin 2009), iDrug (Wang 2014), iStar (Li 2014), e-LEA3D (Douguet 2010), and MTiOpenScreen (Labbé 2015), are typically batch-processing services where the user submits a virtual screening job and receives the results hours or days later. They are also usually limited to screening a pre-determined library of compounds of limited size. Alternatively, advanced algorithms enable interactive time-scale searches, but existing web resources (Koes 2012, Koes 2012a) are limited by a single search modality and a restricted search domain. In contrast, Pharmit provides both pharmacophore and molecular shape search modalities as well as ranking of results by energy minimization, and, in addition to providing a variety of pre-built compound libraries, allows users to upload their own compound libraries for screening.

    Pharmit takes as its input a predefined pharmacophore query or can elucidate pharmacophore and shape queries from receptor and/or ligand structures. Structures may be provided by the user or extracted directly from the Protein Data Bank (PDB). Pharmacophore and/or molecular shape queries are created and edited in a modern interactive interface powered by 3Dmol.js (Rego 2014), which provides high performance 3D molecular graphics without the need for plugins or Java. Once a query is defined, the user selects and searches a compound library for matching compounds. Results are typically returned in seconds and are displayed in-browser. A variety of filtering and ranking criteria can be applied, and hits can be further refined and ranked using energy minimization. Structure files of the query-optimized hit compounds can be downloaded, and the full session state can be saved and restored. In total, Pharmit provides a comprehensive online platform for structure-based virtual screening.

    \label{pharmfig} Pharmacophore as primary query. Each pharmacophore feature has a collapsible menu in the Pharmacophore panel (left) where its type, location, and radius, as well as number of atoms (for hydrophobic features) or directionality (if relevant) can be defined. Selected features are shown as solid spheres and unselected features as meshes. Filters may be set to reduce the number of hits by constraining the number of hits returned for a given conformer or molecule or the overall number of hits. Selecting a hit in the results panel (right) displays it, and its appearance can be adjusted in the visualization filter along with other aspects of the visual display. For example, here the query ligand is shown in light gray, and the selected hit compound is shown in cyan. This query against tyrosine-protein kinase c-Src (PDB 2SRC) is available on the Pharmit Examples page.