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  1. Article ; Online: Prot2Prot: a deep learning model for rapid, photorealistic macromolecular visualization.

    Durrant, Jacob D

    Journal of computer-aided molecular design

    2022  Volume 36, Issue 9, Page(s) 677–686

    Abstract: Molecular visualization is a cornerstone of structural biology, providing insights into the form and function of biomolecules that are difficult to achieve any other way. Scientific analysis, publication, education, and outreach often benefit from ... ...

    Abstract Molecular visualization is a cornerstone of structural biology, providing insights into the form and function of biomolecules that are difficult to achieve any other way. Scientific analysis, publication, education, and outreach often benefit from photorealistic molecular depictions rendered using advanced computer-graphics programs such as Maya, 3ds Max, and Blender. However, setting up molecular scenes in these programs is laborious even for expert users, and rendering often requires substantial time and computer resources. We have created a deep-learning model called Prot2Prot that quickly imitates photorealistic visualization styles, given a much simpler, easy-to-generate molecular representation. The resulting images are often indistinguishable from images rendered using industry-standard 3D graphics programs, but they can be created in a fraction of the time, even when running in a web browser. To the best of our knowledge, Prot2Prot is the first example of image-to-image translation applied to macromolecular visualization. Prot2Prot is available free of charge, released under the terms of the Apache License, Version 2.0. Users can access a Prot2Prot-powered web app without registration at http://durrantlab.com/prot2prot .
    MeSH term(s) Computer Graphics ; Deep Learning ; Macromolecular Substances ; Software
    Chemical Substances Macromolecular Substances
    Language English
    Publishing date 2022-08-26
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 808166-9
    ISSN 1573-4951 ; 0920-654X
    ISSN (online) 1573-4951
    ISSN 0920-654X
    DOI 10.1007/s10822-022-00471-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Worth the Weight: Sub-Pocket EXplorer (SubPEx), a Weighted Ensemble Method to Enhance Binding-Pocket Conformational Sampling.

    Hellemann, Erich / Durrant, Jacob D

    Journal of chemical theory and computation

    2023  Volume 19, Issue 17, Page(s) 5677–5689

    Abstract: Structure-based virtual screening (VS) is an effective method for identifying potential small-molecule ligands, but traditional VS approaches consider only a single binding-pocket conformation. Consequently, they struggle to identify ligands that bind to ...

    Abstract Structure-based virtual screening (VS) is an effective method for identifying potential small-molecule ligands, but traditional VS approaches consider only a single binding-pocket conformation. Consequently, they struggle to identify ligands that bind to alternate conformations. Ensemble docking helps address this issue by incorporating multiple conformations into the docking process, but it depends on methods that can thoroughly explore pocket flexibility. We here introduce Sub-Pocket EXplorer (SubPEx), an approach that uses weighted ensemble (WE) path sampling to accelerate binding-pocket sampling. As proof of principle, we apply SubPEx to three proteins relevant to drug discovery: heat shock protein 90, influenza neuraminidase, and yeast hexokinase 2. SubPEx is available free of charge without registration under the terms of the open-source MIT license: http://durrantlab.com/subpex/.
    MeSH term(s) Protein Conformation ; Ligands ; Proteins/metabolism ; Drug Discovery ; Binding Sites ; Molecular Docking Simulation ; Protein Binding
    Chemical Substances Ligands ; Proteins
    Language English
    Publishing date 2023-08-16
    Publishing country United States
    Document type Journal Article
    ISSN 1549-9626
    ISSN (online) 1549-9626
    DOI 10.1021/acs.jctc.3c00478
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  3. Article: Worth the weight: Sub-Pocket EXplorer (SubPEx), a weighted-ensemble method to enhance binding-pocket conformational sampling.

    Hellemann, Erich / Durrant, Jacob D

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Structure-based virtual screening (VS) is an effective method for identifying potential small-molecule ligands, but traditional VS approaches consider only a single binding-pocket conformation. Consequently, they struggle to identify ligands that bind to ...

    Abstract Structure-based virtual screening (VS) is an effective method for identifying potential small-molecule ligands, but traditional VS approaches consider only a single binding-pocket conformation. Consequently, they struggle to identify ligands that bind to alternate conformations. Ensemble docking helps address this issue by incorporating multiple conformations into the docking process, but it depends on methods that can thoroughly explore pocket flexibility. We here introduce Sub-Pocket EXplorer (SubPEx), an approach that uses weighted ensemble (WE) path sampling to accelerate binding-pocket sampling. As proof of principle, we apply SubPEx to three proteins relevant to drug discovery: heat shock protein 90, influenza neuraminidase, and yeast hexokinase 2. SubPEx is available free of charge without registration under the terms of the open-source MIT license: http://durrantlab.com/subpex/.
    Language English
    Publishing date 2023-05-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.05.03.539330
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  4. Article ; Online: From byte to bench to bedside: molecular dynamics simulations and drug discovery.

    Ahmed, Mayar / Maldonado, Alex M / Durrant, Jacob D

    BMC biology

    2023  Volume 21, Issue 1, Page(s) 299

    MeSH term(s) Molecular Dynamics Simulation ; Drug Discovery
    Language English
    Publishing date 2023-12-29
    Publishing country England
    Document type Letter
    ZDB-ID 2133020-7
    ISSN 1741-7007 ; 1741-7007
    ISSN (online) 1741-7007
    ISSN 1741-7007
    DOI 10.1186/s12915-023-01791-z
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  5. Article: FPocketWeb: protein pocket hunting in a web browser.

    Kochnev, Yuri / Durrant, Jacob D

    Journal of cheminformatics

    2022  Volume 14, Issue 1, Page(s) 58

    Abstract: Detecting macromolecular (e.g., protein) cavities where small molecules bind is an early step in computer-aided drug discovery. Multiple pocket-detection algorithms have been developed over the past several decades. Among them, fpocket, created by ... ...

    Abstract Detecting macromolecular (e.g., protein) cavities where small molecules bind is an early step in computer-aided drug discovery. Multiple pocket-detection algorithms have been developed over the past several decades. Among them, fpocket, created by Schmidtke and Le Guilloux, is particularly popular. Like many programs used in computational-biology research, fpocket requires users to download and install an executable file. That file must also be run via a command-line interface, further complicating use. An existing fpocket server application effectively addresses these challenges, but it requires users to upload their possibly proprietary structures to a third-party server. The FPocketWeb web app builds on this prior work. It runs the fpocket3 executable entirely in a web browser without requiring installation. The pocket-finding calculations occur on the user's computer rather than on a remote server. A working version of the open-source FPocketWeb app can be accessed free of charge from http://durrantlab.com/fpocketweb .
    Language English
    Publishing date 2022-08-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 2486539-4
    ISSN 1758-2946
    ISSN 1758-2946
    DOI 10.1186/s13321-022-00637-0
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  6. Article ; Online: Open-Source Browser-Based Tools for Structure-Based Computer-Aided Drug Discovery.

    Wang, Ann / Durrant, Jacob D

    Molecules (Basel, Switzerland)

    2022  Volume 27, Issue 14

    Abstract: We here outline the importance of open-source, accessible tools for computer-aided drug discovery (CADD). We begin with a discussion of drug discovery in general to provide context for a subsequent discussion of structure-based CADD applied to small- ... ...

    Abstract We here outline the importance of open-source, accessible tools for computer-aided drug discovery (CADD). We begin with a discussion of drug discovery in general to provide context for a subsequent discussion of structure-based CADD applied to small-molecule ligand discovery. Next, we identify usability challenges common to many open-source CADD tools. To address these challenges, we propose a browser-based approach to CADD tool deployment in which CADD calculations run in modern web browsers on users' local computers. The browser app approach eliminates the need for user-initiated download and installation, ensures broad operating system compatibility, enables easy updates, and provides a user-friendly graphical user interface. Unlike server apps-which run calculations "in the cloud" rather than on users' local computers-browser apps do not require users to upload proprietary information to a third-party (remote) server. They also eliminate the need for the difficult-to-maintain computer infrastructure required to run user-initiated calculations remotely. We conclude by describing some CADD browser apps developed in our lab, which illustrate the utility of this approach. Aside from introducing readers to these specific tools, we are hopeful that this review highlights the need for additional browser-compatible, user-friendly CADD software.
    MeSH term(s) Computers ; Drug Discovery ; Internet ; Ligands ; Software ; User-Computer Interface ; Web Browser
    Chemical Substances Ligands
    Language English
    Publishing date 2022-07-20
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules27144623
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  7. Article ; Online: From Byte to Bench to Bedside: Molecular Dynamics Simulations and Drug Discovery.

    Ahmed, Mayar / Maldonado, Alex M / Durrant, Jacob D

    ArXiv

    2023  

    Abstract: 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 ... ...

    Abstract 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.
    Language English
    Publishing date 2023-11-28
    Publishing country United States
    Document type Preprint
    ISSN 2331-8422
    ISSN (online) 2331-8422
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  8. Article: CENsible: Interpretable Insights into Small-Molecule Binding with Context Explanation Networks.

    Bhatt, Roshni / Koes, David Ryan / Durrant, Jacob D

    bioRxiv : the preprint server for biology

    2023  

    Abstract: We present a novel and interpretable approach for predicting small-molecule binding affinities using context explanation networks (CENs). Given the specific structure of a protein/ligand complex, our CENsible scoring function uses a deep convolutional ... ...

    Abstract We present a novel and interpretable approach for predicting small-molecule binding affinities using context explanation networks (CENs). Given the specific structure of a protein/ligand complex, our CENsible scoring function uses a deep convolutional neural network to predict the contributions of pre-calculated terms to the overall binding affinity. We show that CENsible can effectively distinguish active vs. inactive compounds for many systems. Its primary benefit over related machine-learning scoring functions, however, is that it retains interpretability, allowing researchers to identify the contribution of each pre-calculated term to the final affinity prediction, with implications for subsequent lead optimization.
    Language English
    Publishing date 2023-10-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.18.562959
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  9. Article ; Online: Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.

    Hellemann, Erich / Nallathambi, Amrita / Durrant, Jacob D

    Protein science : a publication of the Protein Society

    2023  Volume 32, Issue 4, Page(s) e4622

    Abstract: β-lactam antibiotics target DD-transpeptidases, enzymes that perform the last step of bacterial cell-wall synthesis. To block the antimicrobial activity of these antibiotics, bacteria have evolved lactamases that render them inert. Among these, TEM-1, a ... ...

    Abstract β-lactam antibiotics target DD-transpeptidases, enzymes that perform the last step of bacterial cell-wall synthesis. To block the antimicrobial activity of these antibiotics, bacteria have evolved lactamases that render them inert. Among these, TEM-1, a class A lactamase, has been extensively studied. In 2004, Horn et al. described a novel allosteric TEM-1 inhibitor, FTA, that binds distant from the TEM-1 orthosteric (penicillin-binding) pocket. TEM-1 has subsequently become a model for the study of allostery. In the present work, we perform molecular dynamics simulations of FTA-bound and FTA-absent TEM-1, totaling ~3 μS, that provide new insight into TEM-1 inhibition. In one of the simulations, bound FTA assumed a conformation different than that observed crystallographically. We provide evidence that the alternate pose is physiologically plausible and describe how it impacts our understanding of TEM-1 allostery.
    MeSH term(s) Molecular Dynamics Simulation ; beta-Lactamases/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacteria/metabolism ; Penicillins
    Chemical Substances beta-Lactamases (EC 3.5.2.6) ; Anti-Bacterial Agents ; Penicillins
    Language English
    Publishing date 2023-03-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1002/pro.4622
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    Zs.A 3407: Show issues Location:
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    Zs.MO 1: Show issues

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  10. Article ; Online: Computational and experimental analyses of alanine racemase suggest new avenues for developing allosteric small-molecule antibiotics.

    van Wieren, Arie / Durrant, Jacob D / Majumdar, Sudipta

    Drug development research

    2023  Volume 84, Issue 5, Page(s) 999–1007

    Abstract: Given the ever-present threat of antibacterial resistance, there is an urgent need to identify new antibacterial drugs and targets. One such target is alanine racemase (Alr), an enzyme required for bacterial cell-wall biosynthesis. Alr is an attractive ... ...

    Abstract Given the ever-present threat of antibacterial resistance, there is an urgent need to identify new antibacterial drugs and targets. One such target is alanine racemase (Alr), an enzyme required for bacterial cell-wall biosynthesis. Alr is an attractive drug target because it is essential for bacterial survival but is absent in humans. Existing drugs targeting Alr lack specificity and have severe side effects. We here investigate alternative mechanisms of Alr inhibition. Alr functions exclusively as an obligate homodimer, so we probed seven conserved interactions on the dimer interface, distant from the enzymatic active site, to identify possible allosteric influences on activity. Using the Alr from Mycobacterium tuberculosis (MT) as a model, we found that the Lys261/Asp135 salt bridge is critical for catalytic activity. The Lys261Ala mutation completely inactivated the enzyme, and the Asp135Ala mutation reduced catalytic activity eight-fold. Further investigation suggested a potential drug-binding site near the Lys261/Asp135 salt bridge that may be useful for allosteric drug discovery.
    MeSH term(s) Humans ; Anti-Bacterial Agents/pharmacology ; Alanine Racemase/genetics ; Alanine Racemase/chemistry ; Alanine Racemase/metabolism ; Catalytic Domain ; Mycobacterium tuberculosis/genetics ; Drug Resistance, Bacterial
    Chemical Substances Anti-Bacterial Agents ; Alanine Racemase (EC 5.1.1.1)
    Language English
    Publishing date 2023-05-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604587-x
    ISSN 1098-2299 ; 0272-4391
    ISSN (online) 1098-2299
    ISSN 0272-4391
    DOI 10.1002/ddr.22068
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