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The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein–ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTConfronting Racism in Chemistry JournalsCynthia J. BurrowsCynthia J. BurrowsMore by Cynthia J. Burrowshttp://orcid.org/0000-0001-7253-8529, Jiaxing HuangJiaxing HuangMore by Jiaxing Huanghttp://orcid.org/0000-0001-9176-8901, Shu WangShu WangMore by Shu Wanghttp://orcid.org/0000-0001-8781-2535, Hyun Jae KimHyun Jae KimMore by Hyun Jae Kimhttp://orcid.org/0000-0002-6879-9256, Gerald J. MeyerGerald J. MeyerMore by Gerald J. Meyerhttp://orcid.org/0000-0002-4227-6393, Kirk SchanzeKirk SchanzeMore by Kirk Schanzehttp://orcid.org/0000-0003-3342-4080, T. Randall LeeT. Randall LeeMore by T. Randall Leehttp://orcid.org/0000-0001-9584-8861, Jodie L. LutkenhausJodie L. LutkenhausMore by Jodie L. Lutkenhaushttp://orcid.org/0000-0002-2613-6016, David KaplanDavid KaplanMore by David Kaplanhttp://orcid.org/0000-0002-9245-7774, Christopher JonesChristopher JonesMore by Christopher Joneshttp://orcid.org/0000-0003-3255-5791, Carolyn BertozziCarolyn BertozziMore by Carolyn Bertozzihttp://orcid.org/0000-0003-4482-2754, Laura KiesslingLaura KiesslingMore by Laura Kiesslinghttp://orcid.org/0000-0001-6829-1500, Mary Beth MulcahyMary Beth MulcahyMore by Mary Beth Mulcahyhttp://orcid.org/0000-0002-3060-9189, Craig W. LindsleyCraig W. LindsleyMore by Craig W. Lindsleyhttp://orcid.org/0000-0003-0168-1445, M. G. FinnM. G. FinnMore by M. G. Finnhttp://orcid.org/0000-0001-8247-3108, Joel D. BlumJoel D. BlumMore by Joel D. Blumhttp://orcid.org/0000-0001-5389-8633, Prashant KamatPrashant KamatMore by Prashant Kamathttp://orcid.org/0000-0002-2465-6819, Wonyong ChoiWonyong ChoiMore by Wonyong Choihttp://orcid.org/0000-0003-1801-9386, Shane SnyderShane SnyderMore by Shane Snyderhttp://orcid.org/0000-0003-2709-9840, Courtney C. AldrichCourtney C. AldrichMore by Courtney C. Aldrichhttp://orcid.org/0000-0001-9261-594X, Stuart RowanStuart RowanMore by Stuart Rowanhttp://orcid.org/0000-0001-8176-0594, Bin LiuBin LiuMore by Bin Liuhttp://orcid.org/0000-0002-0956-2777, Dennis LiottaDennis LiottaMore by Dennis Liottahttp://orcid.org/0000-0002-7736-7113, Paul S. WeissPaul S. WeissMore by Paul S. Weisshttp://orcid.org/0000-0001-5527-6248, Deqing ZhangDeqing ZhangMore by Deqing Zhanghttp://orcid.org/0000-0002-5709-6088, Krishna N. GaneshKrishna N. GaneshMore by Krishna N. Ganeshhttp://orcid.org/0000-0003-2292-643X, Harry A. AtwaterHarry A. AtwaterMore by Harry A. Atwaterhttp://orcid.org/0000-0001-9435-0201, J. Justin GoodingJ. Justin GoodingMore by J. Justin Goodinghttp://orcid.org/0000-0002-5398-0597, David T. AllenDavid T. AllenMore by David T. Allenhttp://orcid.org/0000-0001-6646-8755, Christopher A. VoigtChristopher A. VoigtMore by Christopher A. Voigthttp://orcid.org/0000-0003-0844-4776, Jonathan SweedlerJonathan SweedlerMore by Jonathan Sweedlerhttp://orcid.org/0000-0003-3107-9922, Alanna SchepartzAlanna SchepartzMore by Alanna Schepartzhttp://orcid.org/0000-0003-2127-3932, Vincent RotelloVincent RotelloMore by Vincent Rotellohttp://orcid.org/0000-0002-5184-5439, Sébastien LecommandouxSébastien LecommandouxMore by Sébastien Lecommandouxhttp://orcid.org/0000-0003-0465-8603, Shana J. SturlaShana J. SturlaMore by Shana J. Sturlahttp://orcid.org/0000-0001-6808-5950, Sharon Hammes-SchifferSharon Hammes-SchifferMore by Sharon Hammes-Schifferhttp://orcid.org/0000-0002-3782-6995, Jillian BuriakJillian BuriakMore by Jillian Buriakhttp://orcid.org/0000-0002-9567-4328, Jonathan W. SteedJonathan W. SteedMore by Jonathan W. Steedhttp://orcid.org/0000-0002-7466-7794, Hongwei WuHongwei WuMore by Hongwei Wuhttp://orcid.org/0000-0002-2816-749X, Julie ZimmermanJulie ZimmermanMore by Julie Zimmermanhttp://orcid.org/0000-0002-5392-312X, Bryan BrooksBryan BrooksMore by Bryan Brookshttp://orcid.org/0000-0002-6277-9852, Phillip SavagePhillip SavageMore by Phillip Savagehttp://orcid.org/0000-0002-7902-3744, William TolmanWilliam TolmanMore by William Tolmanhttp://orcid.org/0000-0002-2243-6409, Thomas F. HofmannThomas F. HofmannMore by Thomas F. Hofmannhttp://orcid.org/0000-0003-4057-7165, Joan F. BrenneckeJoan F. BrenneckeMore by Joan F. Brenneckehttp://orcid.org/0000-0002-7935-2134, Thomas A. HolmeThomas A. HolmeMore by Thomas A. Holmehttp://orcid.org/0000-0003-0590-5848, Kenneth M. Merz Jr.Kenneth M. Merz, Jr.More by Kenneth M. Merz, Jr.http://orcid.org/0000-0001-9139-5893, Gustavo ScuseriaGustavo ScuseriaMore by Gustavo Scuseriahttp://orcid.org/0000-0002-4635-8126, William JorgensenWilliam JorgensenMore by William Jorgensenhttp://orcid.org/0000-0002-3993-9520, Gunda I. GeorgGunda I. GeorgMore by Gunda I. Georghttp://orcid.org/0000-0002-8900-9460, Shaomeng WangShaomeng WangMore by Shaomeng Wanghttp://orcid.org/0000-0002-8782-6950, Philip ProteauPhilip ProteauMore by Philip Proteauhttp://orcid.org/0000-0001-7791-8854, John R. Yates IIIJohn R. Yates, IIIMore by John R. Yates, IIIhttp://orcid.org/0000-0001-5267-1672, Peter StangPeter StangMore by Peter Stanghttp://orcid.org/0000-0002-2307-0576, Gilbert C. WalkerGilbert C. WalkerMore by Gilbert C. Walkerhttp://orcid.org/0000-0002-5248-5498, Marc HillmyerMarc HillmyerMore by Marc Hillmyerhttp://orcid.org/0000-0001-8255-3853, Lynne S. TaylorLynne S. TaylorMore by Lynne S. Taylorhttp://orcid.org/0000-0002-4568-6021, Teri W. OdomTeri W. OdomMore by Teri W. Odomhttp://orcid.org/0000-0002-8490-292X, Erick CarreiraErick CarreiraMore by Erick Carreirahttp://orcid.org/0000-0003-1472-490X, Kai RossenKai RossenMore by Kai Rossenhttp://orcid.org/0000-0002-3857-0004, Paul ChirikPaul ChirikMore by Paul Chirikhttp://orcid.org/0000-0001-8473-2898, Scott J. MillerScott J. MillerMore by Scott J. Millerhttp://orcid.org/0000-0001-7817-1318, Joan-Emma SheaJoan-Emma SheaMore by Joan-Emma Sheahttp://orcid.org/0000-0002-9801-9273, Anne McCoyAnne McCoyMore by Anne McCoyhttp://orcid.org/0000-0001-6851-6634, Martin ZanniMartin ZanniMore by Martin Zannihttp://orcid.org/0000-0001-7191-9768, Gregory HartlandGregory HartlandMore by Gregory Hartlandhttp://orcid.org/0000-0002-8650-6891, Gregory ScholesGregory ScholesMore by Gregory Scholeshttp://orcid.org/0000-0003-3336-7960, Joseph A. LooJoseph A. LooMore by Joseph A. Loohttp://orcid.org/0000-0001-9989-1437, James MilneJames MilneMore by James Milnehttp://orcid.org/0000-0002-2119-2377, Sarah B. TegenSarah B. TegenMore by Sarah B. Tegenhttp://orcid.org/0000-0001-8618-2666, Daniel T. KulpDaniel T. KulpMore by Daniel T. Kulphttp://orcid.org/0000-0003-1147-2196, and Julia LaskinJulia LaskinMore by Julia Laskinhttp://orcid.org/0000-0002-4533-9644Cite this: ACS Energy Lett. 2020, 5, 7, 2291–2293Publication Date (Web):June 19, 2020Publication History Received16 June 2020Accepted16 June 2020Published online19 June 2020Published inissue 10 July 2020https://pubs.acs.org/doi/10.1021/acsenergylett.0c01302https://doi.org/10.1021/acsenergylett.0c01302editorialACS PublicationsCopyright © 2020 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views795Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (2 MB) Get e-AlertscloseSUBJECTS:Computational chemistry,Interfaces,Materials,Mathematical methods Get e-Alerts

Combination antiretroviral therapy (cART) has been proven effective in inhibiting human immunodeficiency virus type 1 (HIV-1) infection and has significantly improved the health outcomes in acquired immune deficiency syndrome (AIDS) patients. The therapeutic benefits of cART have been challenged because of the toxicity and emergence of drug-resistant HIV-1 strains along with lifelong patient compliance resulting in non-adherence. These issues also hinder the clinical benefits of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are one of the vital components of cART for the treatment of HIV-1 infection. In this study, using a computational and structural based drug design approach, we have discovered an effective HIV -1 NNRTI, compound I (Cmpd I) that is very potent in biochemical assays and which targets key residues in the allosteric binding pocket of wild-type (WT)-RT as revealed by structural studies. Furthermore, Cmpd I exhibited very potent antiviral activity in HIV-1 infected T cells, lacked cytotoxicity (therapeutic index >100,000), and no significant off-target effects were noted in pharmacological assays. To address the issue of non-adherence, we developed a long-acting nanoformulation of Cmpd I (Cmpd I-NP) using poly (lactide-coglycolide) (PLGA) particles. The pharmacokinetic studies of free and nanoformulated Cmpd I were carried out in BALB/c mice. Intraperitoneal administration of Cmpd I and Cmpd I-NP in BALB/c mice revealed prolonged serum residence time of 48 h and 30 days, respectively. The observed serum concentrations of Cmpd I in both cases were sufficient to provide >97% inhibition in HIV-1 infected T-cells. The significant antiviral activity along with favorable pharmacological and pharmacokinetic profile of Cmpd I, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.

Optimization of thienopyrimidinone derivatives as FGFR1 kinase inhibitors is being pursued. The present results confirm predictions of computational modeling that an aryl substituent can be introduced at the 2-position in structure 3. The substituent is anticipated to project deeper into the binding site and provide opportunities for enhanced activity and selectivity. The most potent analog reported herein, 13, has a 4-hydroxyphenyl substituent and yields an IC50 of 6μM for inhibition of phosphorylation by FGFR1 kinase. It was also found that the western anisole-containing substituent in 3 can be replaced by a propionic acid group with no loss in potency and with potentially significant gains in pharmacologically relevant properties.

Folded polymers are used in Nature for virtually every vital process. Nonnatural folded polymers, or foldamers, have the potential for similar versatility, and the design and refinement of such molecules is of considerable current interest. Here we report a complete and systematic analysis of the relationship between side chain structure and the 14-helicity of a well-studied class of foldamers, β3-peptides, in water. Our experimental results (1) verify the importance of macrodipole stabilization for maintaining 14-helix structure, (2) provide comprehensive evidence that β3-amino acids branched at the first side chain carbon are 14-helix-stabilizing, (3) suggest a novel role for side chain hydrogen bonding as an additional stabilizing force in β3-peptides containing β3-homoserine or β3-homothreonine, and (4) demonstrate that diverse functionality can be incorporated into a stable 14-helix. Gas- and solution-phase calculations and Monte Carlo simulations recapitulate the experimental trends only in the context of oligomers, yielding insight into the mechanisms behind 14-helix folding. The 14-helix propensities of β3-amino acids differ starkly from the α-helix propensities of analogous α-amino acids. This contrast informs current models for α-helix folding, and suggests that 14-helix folding is governed by different biophysical forces than is α-helix folding. The ability to modulate 14-helix structure through side chain choice will assist rational design of 14-helical β-peptide ligands for macromolecular targets.

With standard scoring methods, top-ranked compounds from virtual screening by docking often turn out to be inactive. For this reason, metadynamics, a method used to sample rare events, was studied to further evaluate docking poses with the aim of reducing false positives. Specifically, virtual screening was performed with Glide SP to seek potential molecules to bind to the ATP site in the pseudokinase domain of JAK2 kinase, and promising compounds were selected from the top-ranked 1000 based on visualization. Rescoring with Glide XP, GOLD, and MM/GBSA was unable to differentiate well between active and inactive compounds. Metadynamics was then used to gauge the relative binding affinity from the required time or the potential of mean force needed to dissociate the ligand from the bound complex. With consideration of previously known binders of varying affinities, metadynamics was able to differentiate between the most active compounds and inactive or weakly active ones, and it could identify correctly most of the selected virtual screening compounds as false positives. Thus, metadynamics has the potential to be a viable postprocessing method for virtual screening, minimizing the expense of buying or synthesizing inactive compounds.

To discover non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that are effective against both wild-type (WT) virus and variants that encode the clinically troublesome Tyr181Cys (Y181C) RT mutation, virtual screening by docking was carried out using three RT structures and more than 2 million commercially available compounds. Two of the structures are for WT-virus with different conformations of Tyr181, while the third structure incorporates the Y181C modification. Eventually nine compounds were purchased and assayed. Three of the compounds show low-micromolar antiviral activity toward either or both the wild-type and Y181C HIV-1 strains. The study illustrates a viable protocol to seek anti-HIV agents with enhanced resistance profiles.

The generation of a complete ensemble of geometrical configurations is required to obtain reliable estimations of absolute binding free energies by alchemical free energy methods. Molecular dynamics (MD) is the most popular sampling method, but the representation of large biomolecular systems may be incomplete owing to energetic barriers that impede efficient sampling of the configurational space. Monte Carlo (MC) methods can possibly overcome this issue by adapting the attempted movement sizes to facilitate transitions between alternative local-energy minima. In this study, we present an MC statistical mechanics algorithm to explore the protein-ligand conformational space with emphasis on the motions of the protein backbone and side chains. The parameters for each MC move type were optimized to better reproduce conformational distributions of 18 dipeptides and the well-studied T4-lysozyme L99A protein. Next, the performance of the improved MC algorithms was evaluated by computing absolute free energies of binding for L99A lysozyme with benzene and seven analogs. Results for benzene with L99A lysozyme from MD and the optimized MC protocol were found to agree within 0.6 kcal/mol, while a mean unsigned error of 1.2 kcal/mol between MC results and experiment was obtained for the seven benzene analogs. Significant advantages in computation speed are also reported with MC over MD for similar extents of configurational sampling.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPhotoelectron spectra of the 1,2,5,6-tetramethyl-3,4,7,8-tetramethylene derivatives of tricyclo[3.3.0.02,6]octane and tricyclo[4.2.0.02,5]octaneWeston Thatcher Borden, Stanley D. Young, David C. Frost, Nicholas P. C. Westwood, and William L. JorgensenCite this: J. Org. Chem. 1979, 44, 5, 737–740Publication Date (Print):March 1, 1979Publication History Published online1 May 2002Published inissue 1 March 1979https://pubs.acs.org/doi/10.1021/jo01319a016https://doi.org/10.1021/jo01319a016research-articleACS PublicationsRequest reuse permissionsArticle Views63Altmetric-Citations15LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTConfronting Racism in Chemistry JournalsCynthia J. BurrowsCynthia J. BurrowsMore by Cynthia J. Burrowshttp://orcid.org/0000-0001-7253-8529, Jiaxing HuangJiaxing HuangMore by Jiaxing Huanghttp://orcid.org/0000-0001-9176-8901, Shu WangShu WangMore by Shu Wanghttp://orcid.org/0000-0001-8781-2535, Hyun Jae KimHyun Jae KimMore by Hyun Jae Kimhttp://orcid.org/0000-0002-6879-9256, Gerald J. MeyerGerald J. MeyerMore by Gerald J. Meyerhttp://orcid.org/0000-0002-4227-6393, Kirk SchanzeKirk SchanzeMore by Kirk Schanzehttp://orcid.org/0000-0003-3342-4080, T. Randall LeeT. Randall LeeMore by T. Randall Leehttp://orcid.org/0000-0001-9584-8861, Jodie L. LutkenhausJodie L. LutkenhausMore by Jodie L. Lutkenhaushttp://orcid.org/0000-0002-2613-6016, David KaplanDavid KaplanMore by David Kaplanhttp://orcid.org/0000-0002-9245-7774, Christopher JonesChristopher JonesMore by Christopher Joneshttp://orcid.org/0000-0003-3255-5791, Carolyn BertozziCarolyn BertozziMore by Carolyn Bertozzihttp://orcid.org/0000-0003-4482-2754, Laura KiesslingLaura KiesslingMore by Laura Kiesslinghttp://orcid.org/0000-0001-6829-1500, Mary Beth MulcahyMary Beth MulcahyMore by Mary Beth Mulcahyhttp://orcid.org/0000-0002-3060-9189, Craig W. LindsleyCraig W. LindsleyMore by Craig W. Lindsleyhttp://orcid.org/0000-0003-0168-1445, M. G. FinnM. G. FinnMore by M. G. Finnhttp://orcid.org/0000-0001-8247-3108, Joel D. BlumJoel D. BlumMore by Joel D. Blumhttp://orcid.org/0000-0001-5389-8633, Prashant KamatPrashant KamatMore by Prashant Kamathttp://orcid.org/0000-0002-2465-6819, Wonyong ChoiWonyong ChoiMore by Wonyong Choihttp://orcid.org/0000-0003-1801-9386, Shane SnyderShane SnyderMore by Shane Snyderhttp://orcid.org/0000-0003-2709-9840, Courtney C. AldrichCourtney C. AldrichMore by Courtney C. Aldrichhttp://orcid.org/0000-0001-9261-594X, Stuart RowanStuart RowanMore by Stuart Rowanhttp://orcid.org/0000-0001-8176-0594, Bin LiuBin LiuMore by Bin Liuhttp://orcid.org/0000-0002-0956-2777, Dennis LiottaDennis LiottaMore by Dennis Liottahttp://orcid.org/0000-0002-7736-7113, Paul S. WeissPaul S. WeissMore by Paul S. Weisshttp://orcid.org/0000-0001-5527-6248, Deqing ZhangDeqing ZhangMore by Deqing Zhanghttp://orcid.org/0000-0002-5709-6088, Krishna N. GaneshKrishna N. GaneshMore by Krishna N. Ganeshhttp://orcid.org/0000-0003-2292-643X, Harry A. AtwaterHarry A. AtwaterMore by Harry A. Atwaterhttp://orcid.org/0000-0001-9435-0201, J. Justin GoodingJ. Justin GoodingMore by J. Justin Goodinghttp://orcid.org/0000-0002-5398-0597, David T. AllenDavid T. AllenMore by David T. Allenhttp://orcid.org/0000-0001-6646-8755, Christopher A. VoigtChristopher A. VoigtMore by Christopher A. Voigthttp://orcid.org/0000-0003-0844-4776, Jonathan SweedlerJonathan SweedlerMore by Jonathan Sweedlerhttp://orcid.org/0000-0003-3107-9922, Alanna SchepartzAlanna SchepartzMore by Alanna Schepartzhttp://orcid.org/0000-0003-2127-3932, Vincent RotelloVincent RotelloMore by Vincent Rotellohttp://orcid.org/0000-0002-5184-5439, Sébastien LecommandouxSébastien LecommandouxMore by Sébastien Lecommandouxhttp://orcid.org/0000-0003-0465-8603, Shana J. SturlaShana J. SturlaMore by Shana J. Sturlahttp://orcid.org/0000-0001-6808-5950, Sharon Hammes-SchifferSharon Hammes-SchifferMore by Sharon Hammes-Schifferhttp://orcid.org/0000-0002-3782-6995, Jillian BuriakJillian BuriakMore by Jillian Buriakhttp://orcid.org/0000-0002-9567-4328, Jonathan W. SteedJonathan W. SteedMore by Jonathan W. Steedhttp://orcid.org/0000-0002-7466-7794, Hongwei WuHongwei WuMore by Hongwei Wuhttp://orcid.org/0000-0002-2816-749X, Julie ZimmermanJulie ZimmermanMore by Julie Zimmermanhttp://orcid.org/0000-0002-5392-312X, Bryan BrooksBryan BrooksMore by Bryan Brookshttp://orcid.org/0000-0002-6277-9852, Phillip SavagePhillip SavageMore by Phillip Savagehttp://orcid.org/0000-0002-7902-3744, William TolmanWilliam TolmanMore by William Tolmanhttp://orcid.org/0000-0002-2243-6409, Thomas F. HofmannThomas F. HofmannMore by Thomas F. Hofmannhttp://orcid.org/0000-0003-4057-7165, Joan F. BrenneckeJoan F. BrenneckeMore by Joan F. Brenneckehttp://orcid.org/0000-0002-7935-2134, Thomas A. HolmeThomas A. HolmeMore by Thomas A. Holmehttp://orcid.org/0000-0003-0590-5848, Kenneth M. Merz Jr.Kenneth M. Merz, Jr.More by Kenneth M. Merz, Jr.http://orcid.org/0000-0001-9139-5893, Gustavo ScuseriaGustavo ScuseriaMore by Gustavo Scuseriahttp://orcid.org/0000-0002-4635-8126, William JorgensenWilliam JorgensenMore by William Jorgensenhttp://orcid.org/0000-0002-3993-9520, Gunda I. GeorgGunda I. GeorgMore by Gunda I. Georghttp://orcid.org/0000-0002-8900-9460, Shaomeng WangShaomeng WangMore by Shaomeng Wanghttp://orcid.org/0000-0002-8782-6950, Philip ProteauPhilip ProteauMore by Philip Proteauhttp://orcid.org/0000-0001-7791-8854, John R. Yates IIIJohn R. Yates, IIIMore by John R. Yates, IIIhttp://orcid.org/0000-0001-5267-1672, Peter StangPeter StangMore by Peter Stanghttp://orcid.org/0000-0002-2307-0576, Gilbert C. WalkerGilbert C. WalkerMore by Gilbert C. Walkerhttp://orcid.org/0000-0002-5248-5498, Marc HillmyerMarc HillmyerMore by Marc Hillmyerhttp://orcid.org/0000-0001-8255-3853, Lynne S. TaylorLynne S. TaylorMore by Lynne S. Taylorhttp://orcid.org/0000-0002-4568-6021, Teri W. OdomTeri W. OdomMore by Teri W. Odomhttp://orcid.org/0000-0002-8490-292X, Erick CarreiraErick CarreiraMore by Erick Carreirahttp://orcid.org/0000-0003-1472-490X, Kai RossenKai RossenMore by Kai Rossenhttp://orcid.org/0000-0002-3857-0004, Paul ChirikPaul ChirikMore by Paul Chirikhttp://orcid.org/0000-0001-8473-2898, Scott J. MillerScott J. MillerMore by Scott J. Millerhttp://orcid.org/0000-0001-7817-1318, Joan-Emma SheaJoan-Emma SheaMore by Joan-Emma Sheahttp://orcid.org/0000-0002-9801-9273, Anne McCoyAnne McCoyMore by Anne McCoyhttp://orcid.org/0000-0001-6851-6634, Martin ZanniMartin ZanniMore by Martin Zannihttp://orcid.org/0000-0001-7191-9768, Gregory HartlandGregory HartlandMore by Gregory Hartlandhttp://orcid.org/0000-0002-8650-6891, Gregory ScholesGregory ScholesMore by Gregory Scholeshttp://orcid.org/0000-0003-3336-7960, Joseph A. LooJoseph A. LooMore by Joseph A. Loohttp://orcid.org/0000-0001-9989-1437, James MilneJames MilneMore by James Milnehttp://orcid.org/0000-0002-2119-2377, Sarah B. TegenSarah B. TegenMore by Sarah B. Tegenhttp://orcid.org/0000-0001-8618-2666, Daniel T. KulpDaniel T. KulpMore by Daniel T. Kulphttp://orcid.org/0000-0003-1147-2196, and Julia LaskinJulia LaskinMore by Julia Laskinhttp://orcid.org/0000-0002-4533-9644Cite this: Biomacromolecules 2020, 21, 7, 2543–2545Publication Date (Web):June 19, 2020Publication History Published online19 June 2020Published inissue 13 July 2020https://pubs.acs.org/doi/10.1021/acs.biomac.0c00924https://doi.org/10.1021/acs.biomac.0c00924editorialACS PublicationsCopyright © 2020 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1150Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (2 MB) Get e-AlertscloseSUBJECTS:Computational chemistry,Interfaces,Materials,Mathematical methods Get e-Alerts

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.