Journal ArticleDOI
SwissParam: a fast force field generation tool for small organic molecules.
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TLDR
A fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field is presented.Abstract:
The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch.read more
Citations
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Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.
Tatjana Weil,Rüdiger Groß,Annika Röcker,Kenny Bravo-Rodriguez,Christian Heid,Andrea Sowislok,My Hue Le,Nelli Erwin,Mridula Dwivedi,Stephen M. Bart,Paul Bates,Lukas Wettstein,Janis A. Müller,Mirja Harms,Konstantin M. J. Sparrer,Yasser B. Ruiz-Blanco,Christina M. Stürzel,Jens von Einem,Sina Lippold,Clarissa Read,Paul Walther,Marco Hebel,Marco Hebel,Florian Kreppel,Frank-Gerrit Klärner,Gal Bitan,Michael Ehrmann,Tanja Weil,Tanja Weil,Roland Winter,Thomas Schrader,James Shorter,Elsa Sanchez-Garcia,Jan Münch +33 more
TL;DR: The mechanistic basis of viral envelope disruption by specific tweezers is established and a new class of potential broad-spectrum antivirals with enhanced activity is established.
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A structural mechanism for bacterial autotransporter glycosylation by a dodecameric heptosyltransferase family
Qing Yao,Qiuhe Lu,Xiaobo Wan,Feng Song,Yue Xu,Mo Hu,Alla Zamyatina,Xiaoyun Liu,Niu Huang,Ping Zhu,Feng Shao +10 more
TL;DR: It is demonstrated that TibC from ETEC harbors a heptosyltransferase activity on TibA and AIDA-I, defining a large family of bacterial autotransporter heptsyltransferases (BAHTs), and the crystal structure of TibC reveals a characteristic ring-shape dodecamer.
Journal ArticleDOI
Rational design, efficient syntheses and biological evaluation of N,N′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers
George Agelis,Amalia Resvani,Catherine Koukoulitsa,Tereza Tůmová,Jiřina Slaninová,Dimitra Kalavrizioti,Katerina Spyridaki,Antreas Afantitis,Georgia Melagraki,Athanasia Siafaka,Eleni Gkini,Grigorios Megariotis,Simona Golic Grdadolnik,Manthos G. Papadopoulos,Demetrios Vlahakos,Michael E. Maragoudakis,George Liapakis,Thomas Mavromoustakos,John Matsoukas +18 more
TL;DR: Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydphobic cavity, which may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.
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Modeling thermoset polymers using an improved molecular dynamics crosslinking methodology
TL;DR: In this article, an improved proximity-based molecular dynamics technique for modeling the crosslinking of thermoset polymers is presented. And the molecular structures are analyzed based on the incorporation of cure temperature, cutoff distance, and reaction probability into the Arrhenius equation, providing important insights into the pitfalls of some commonly used assumptions in crosslink simulations.
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Role of Leukotriene A4 Hydrolase Aminopeptidase in the Pathogenesis of Emphysema
Mikell Paige,Kan Wang,Marie D. Burdick,Sunhye Park,Josiah Cha,Erin D. Jeffery,Nicholas E. Sherman,Y. Michael Shim +7 more
TL;DR: It is shown that CS exposure promotes the development of CS-induced emphysema by suppressing the enzymatic activities of the LTA4H aminopeptidase in lung tissues and accumulating PGP and neutrophils in the airspaces.
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