Publications

There is great interest in molecules that inhibit the interactions between p53 and its negative regulators hDM2 and hDMX, as such molecules have validated potential against cancers that overexpress one or both of these oncoproteins.1,2 We reported that substituted 3-peptides can inhibit these interactions3,4 and, more recently, that minimally cationic 3-peptides are sufficiently cell permeable to upregulate p53-dependent genes in live cells.5,6 These observations, coupled with the established intracellular stability of -peptides7-9 and the recently reported structures of hDM210 and hDMX,11 motivated us to exploit computational methods to identify -peptides with improved potency and/or selectivity. This exercise successfully identi-fied a new 3-peptide, 53-16, that possess the desirable attributes of high affinity for hDM2 and hDMX and points to the 3,4-dichlorophenyl moiety as a novel determinant of hDMX affinity. Our computational modeling began with the application of Visual

A select series of methyl ether derivatives of vancomcyin aglycon were prepared and examined for antimicrobial activity against vancomycin-sensitive Staphylococcus aureus and vancomycin-resistant Enterococci faecalis as well as their binding affinity for d-Ala-d-Ala and d-Ala-d-Lac. The intent of the study was to elucidate the role selected key methyl groups may play in the improvement of the in vitro antimicrobial profile of the tetra methyl ether derivative of vancomycin aglycon against vancomycin-resistant Enterococci faecalis previously reported. In these studies, methodology for selective derivatization of the A-, B-, and D-ring was developed that defines the relative reactivity of the four phenols of vancomycin aglycon, providing a foundation for future efforts for site-directed modification of the vancomycin aglycon core.

Absolute binding free energy (ABFE) calculations can be an important part of the drug discovery process by identifying molecules that have the potential to be strong binders for a biomolecular target. Recent work has used free energy perturbation (FEP) theory for these calculations, focusing on a set of 16 inhibitors of the severe acute respiratory syndrome coronavirus 2 main protease (Mpro). Herein, the same data set is evaluated by metadynamics (MetaD), four different docking programs, and molecular mechanics with generalized Born and surface area solvation. MetaD yields a Kendall τ distance of 0.28 and Pearson r2 of 0.49, which reflect somewhat less accuracy than that from the ABFE FEP results. Notably, it is demonstrated that an ensemble docking protocol by which each ligand is docked into the 13 crystal structures in this data set provides improved performance, particularly when docking is carried out with Glide XP (Kendall τ distance = 0.20, Pearson r2 = 0.71), Glide SP (Kendall τ distance = 0.19, Pearson r2 = 0.66), or AutoDock 4 (Kendall τ distance = 0.21, Pearson r2 = 0.55). The best results are obtained with "superconsensus" docking by averaging the 52 results for each compound using the 4 docking protocols and all 13 crystal structures (Kendall τ distance = 0.18, Pearson r2 = 0.73).

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionCorrection to Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design StrategyChristopher M. Bailey, Todd J. Sullivan, Pinar Iyidogan, Julian Tirado-Rives, Raymond Chung, Juliana Ruiz-Caro, Ebrahim Mohamed, William L. Jorgensen, Roger Hunter, and Karen S. Anderson*Cite this: J. Med. Chem. 2013, 56, 21, 8953Publication Date (Web):October 18, 2013Publication History Published online18 October 2013Published inissue 14 November 2013https://pubs.acs.org/doi/10.1021/jm401535fhttps://doi.org/10.1021/jm401535fcorrectionACS PublicationsCopyright © 2013 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 Views459Altmetric-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 (108 KB) Get e-Alertsclose Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTUpdate to Our Reader, Reviewer, and Author Communities—April 2020Cynthia J. BurrowsCynthia J. BurrowsMore by Cynthia J. Burrowshttp://orcid.org/0000-0001-7253-8529, 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, 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 Liu Bin 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, Patrick SextonPatrick SextonMore by Patrick Sextonhttp://orcid.org/0000-0001-8902-2473, 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, Anne McCoyAnne McCoyMore by Anne McCoyhttp://orcid.org/0000-0001-6851-6634, Joan-Emma SheaJoan-Emma SheaMore by Joan-Emma Sheahttp://orcid.org/0000-0002-9801-9273, Martin ZanniMartin ZanniMore by Martin Zannihttp://orcid.org/0000-0001-7191-9768, Catherine MurphyCatherine MurphyMore by Catherine Murphyhttp://orcid.org/0000-0001-7066-5575, Gregory ScholesGregory ScholesMore by Gregory Scholeshttp://orcid.org/0000-0003-3336-7960, and Joseph A. LooJoseph A. LooMore by Joseph A. Loohttp://orcid.org/0000-0001-9989-1437Cite this: ACS Appl. Nano Mater. 2020, 3, 5, 3960–3961Publication Date (Web):April 22, 2020Publication History Published online22 April 2020Published inissue 22 May 2020https://pubs.acs.org/doi/10.1021/acsanm.0c01057https://doi.org/10.1021/acsanm.0c01057editorialACS 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 Views837Altmetric-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-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, Jiaxiang HuangJiaxiang HuangMore by Jiaxiang 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 Chem. Health Saf. 2020, 27, 4, 198–200Publication Date (Web):June 19, 2020Publication History Published online19 June 2020Published inissue 27 July 2020https://pubs.acs.org/doi/10.1021/acs.chas.0c00067https://doi.org/10.1021/acs.chas.0c00067editorialACS 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 Views656Altmetric-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

The effect of mutations on amino acid residues L100, V106, and Y181 for unbound HIV-1 reverse transcriptase (RT) and RT bound to nevirapine and efavirenz was investigated using Monte Carlo/free energy perturbation calculations. Using both native and bound crystal structures of RT, mutation of the amino acid residues to both those observed and unobserved in patients was carried out. The results of the calculations revealed that the variant that survives in patients dosed with either nevirapine or efavirenz had a more positive ΔΔG value than other variants that were not observed in patients. These data suggest that the mutation observed in patients is the most effective (the one that binds the drug most weakly) of all possible codon change mutations.

Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small molecule−protein interactions.

The parasite Toxoplasma gondii can lead to toxoplasmosis in those who are immunocompromised. To combat the infection, the enzyme responsible for nucleotide synthesis thymidylate synthase–dihydrofolate reductase (TS–DHFR) is a suitable drug target. We have used virtual screening to determine novel allosteric inhibitors at the interface between the two TS domains. Selected compounds from virtual screening inhibited TS activity. Thus, these results show that allosteric inhibition by small drug-like molecules can occur in T. gondii TS–DHFR and pave the way for new and potent species-specific inhibitors.