Article
Biochemistry & Molecular Biology
David Baker, Stacey R. Gerben, Andrew J. Borst, Derrick R. Hicks, Isabelle Moczygemba, David Feldman, Brian Coventry, Wei Yang, Asim K. Bera, Marcos Miranda, Alex Kang, Hannah Nguyen
Summary: A challenge in designing protein-small-molecule recognition is the destabilization of protein monomers when incorporating cavities suitable for specific recognition. We overcome this challenge by designing binding pockets at off-axis sites on homo-oligomers, allowing for general recognition of asymmetric substrates. Through computational design, we have successfully created proteins with non-symmetrical interfaces that can bind small molecules, providing new possibilities for binding design free from monomer destabilization constraints.
Article
Biochemistry & Molecular Biology
Eric R. Samuels, Irina F. Sevrioukova
Summary: The study identified an optimal head-group spacer length for improving the thermostability and inhibitory effect of CYP3A4, with the lead compound 3h showing the strongest binding and inhibition. The results suggest that a one-atom linker elongation was beneficial, while a two-atom linker extension led to decreased binding and inhibitory strength. The approach used in this study has resulted in the development of structurally simpler inhibitors that are superior to ritonavir.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Artur Meller, Michael Ward, Jonathan Borowsky, Meghana Kshirsagar, Jeffrey M. Lotthammer, Felipe Oviedo, Juan Lavista Ferres, Gregory R. Bowman
Summary: Cryptic pockets, which expand the scope of drug discovery, can now be targeted in proteins that were previously considered undruggable. The authors develop a graph neural network, called PocketMiner, that accurately predicts the formation of cryptic pockets in static structures using molecular simulation data alone, greatly accelerating the search for druggable targets.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Federico Ricci, Rosaria Gitto, Giovanna Pitasi, Laura De Luca
Summary: The merging of distinct computational approaches has led to the discovery of new biologically active compounds with high efficiency in reducing the replication of SARS-CoV-2. By using molecular modeling, the non-structural protein Nsp13 and its druggable surfaces have been identified as potential targets for drug repurposing.
Article
Biochemistry & Molecular Biology
Steven J. Smith, Gary T. Pauly, Katharine Hewlett, Joel P. Schneider, Stephen H. Hughes
Summary: NNRTIs inhibit HIV-1 replication, usually as part of a three-drug combination therapy. Efforts are being made to develop novel NNRTIs to overcome resistance mutations.
CHEMICAL BIOLOGY & DRUG DESIGN
(2021)
Article
Biochemistry & Molecular Biology
Takuya Shirakihara, Hideki Yamaguchi, Tadashi Kondo, Masakazu Yashiro, Ryuichi Sakai
Summary: The study reveals that in diffuse-type gastric cancer cells, transferrin receptor 1 (TfR1) binds and phosphorylates with fibroblast growth factor receptor 2 (FGFR2), promoting cell proliferation and tumorigenicity. This suggests that controlling TfR1 function could serve as a therapeutic target in diffuse-type gastric cancer with activated FGFR2.
Article
Chemistry, Physical
Justin Tze-Yang Ng, Yaw Sing Tan
Summary: This study reports the development of a new method, accelerated ligand-mapping MD (aLMMD), for detecting challenging binding sites. The method is able to detect and sample cryptic pockets and occluded binding sites, and may serve as a general approach for structure-based drug design in proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Multidisciplinary Sciences
Tadatoshi Sato, Christian D. Castro Andrade, Sung-Hee Yoon, Yingshe Zhao, William J. Greenlee, Patricia C. Weber, Usha Viswanathan, John Kulp, Daniel J. Brooks, Marie B. Demay, Mary L. Bouxsein, Bruce Mitlak, Beate Lanske, Marc N. Wein
Summary: This study identifies SIK2/SIK3 as potential drug targets for treating osteoporosis and successfully develops an orally available SIK2/SIK3 inhibitor. The inhibitor stimulates bone formation and increases bone density without apparent toxicity. These findings provide a new approach for the pharmacological treatment of osteoporosis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Physical
Mikolai Fajer, Ken Borrelli, Robert Abel, Lingle Wang
Summary: Structure-based drug design often assumes a single relevant holo structure, but multiple conformations have been observed in crystallographic examples. The protein reorganization free energy is crucial for accurately predicting binding free energies and designing ligands with stronger potency and selectivity. In this study, we present a computational method to quantify protein reorganization free energies and demonstrate its effectiveness in two drug design cases. This method will enhance computer-aided drug design for complex protein targets.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Jothi Anantharajan, Nithya Baburajendran, Grace Lin, Yong Yao Loh, Weijun Xu, Nur Huda Binte Ahmad, Shuang Liu, Anna E. Jasson, John Wee Liang Kuan, Elizabeth Yihui Ng, Yee Khoon Yeo, Alvin W. Hung, Joma Joy, Jeffrey Hill, Heide L. Ford, Rui Zhao, Thomas H. Keller, CongBao Kang
Summary: This study demonstrated that the inhibitor-bound form of EYA2 does not favor binding to Mg2+, essential for its Tyr phosphatase activity, and described the optimization and characterization of allosteric inhibitors. Through synthesis of analogues, potency of inhibitors was improved and structure-activity relationships were elucidated. Co-crystal structures confirmed binding modes of inhibitors, providing insight into molecular interactions and potential for structure-based drug discovery.
Article
Biochemistry & Molecular Biology
Shanghua Fan, Shanti Pal Gangwar, Mischa Machius, Gabby Rudenko
Summary: This study reveals the molecular basis of a regulatory network formed by the proteins Hevin, SPARC, and MDGA, showing that Hevin competes with SPARC and MDGA to regulate synaptogenic effects and extracellular matrix interactions by binding to overlapping sites on neuroligin.
Article
Chemistry, Medicinal
Francini Fonseca Lopez, Jiayuan Miao, Jovan Damjanovic, Luca Bischof, Michael B. Braun, Yingjie Ling, Marcus D. Hartmann, Yu-Shan Lin, Joshua A. Kritzer
Summary: The Nrf2 transcription factor regulates the response to oxidative stress, and Keap1 is its main negative regulator. This study used molecular dynamics simulations to predict the preorganization of cyclic peptides and correlated it with binding affinities for Keap1. The findings provide insights into designing selective inhibitors of protein-protein interactions using cyclic peptides.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Tae Su Choi, F. Akif Tezcan
Summary: Selective metal binding is crucial for the functions and applications of natural and artificial metalloproteins. A flexible/probabilistic protein design strategy allows the optimal coordination geometry of metal ions to be achieved. In this study, a new flexible protein dimer, B2, was designed and characterized to selectively bind ZnII over other metal ions. The results highlight the utility of protein flexibility in the design and discovery of selective binding motifs.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Sung-Min Kang, Chenglong Jin, Do-Hee Kim, Sung Jean Park, Sang-Woo Han, Bong-Jin Lee
Summary: This study reveals a novel antimicrobial agent that activates HigB toxin to degrade mRNA as an antibacterial strategy against antibiotic-resistant Streptococcus pneumoniae, with a mechanism different from current antibiotics. Additionally, the structure of the HigBA complex and potential catalytic residues of HigB were identified, providing insights into the transcriptional regulation mechanisms and allosteric inhibition of HigB activity.
Article
Biochemistry & Molecular Biology
Sumin Kim, Injeoung Hwang, Suhn Hyung Kim, Hwan Won Chung, Mi-Jung Ji, Sojeong Moon, Hyun-Mee Park, Gu Kong, Wooyoung Hur
Summary: NSD3/WHSC1L1 lysine methyltransferase promotes gene transcription through methylation at histone H3K36 using SAM as a cofactor. NSD3 alterations are oncogenic drivers in cancers like squamous cell lung and breast cancer. We identified a novel class of NSD3 inhibitors through virtual library screening and medicinal chemistry optimization. The most potent analogue, 13i, inhibits NSD3 activity in vitro, suppresses breast cancer cell proliferation, and decreases H3K36me2/3 levels.
CHEMICAL BIOLOGY & DRUG DESIGN
(2023)
Article
Oncology
Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Chris Carpenter, Alan P. Graves, Liling Warren, Zhengyu Xue, Karen S. King, Dana J. Fraser, Sandy Stinnett, Linda P. Briley, Ionel Mitrica, Colin F. Spraggs, Matthew R. Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz, Lini N. Pandite
CLINICAL CANCER RESEARCH
(2016)
Article
Chemistry, Medicinal
Brian G. Lawhorn, Joanne Philp, Yongdong Zhao, Christopher Louer, Marlys Hammond, Mui Cheung, Harvey Fries, Alan P. Graves, Lisa Shewchuk, Liping Wang, Joshua E. Cottom, Hongwei Qi, Huizhen Zhao, Rachel Totoritis, Guofeng Zhang, Benjamin Schwartz, Hu Li, Sharon Sweitzer, Dennis A. Holt, Gregory J. Gatto, Lara S. Kallander
JOURNAL OF MEDICINAL CHEMISTRY
(2015)
Article
Chemistry, Medicinal
Brian G. Lawhorn, Joanne Philp, Alan P. Graves, Lisa Shewchuk, Dennis A. Holt, Gregory J. Gatto, Lara S. Kallander
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2016)
Article
Chemistry, Medicinal
Brian G. Lawhorn, Joanne Philp, Alan P. Graves, Dennis A. Holt, Gregory J. Gatto, Lara S. Kallander
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Biochemical Research Methods
Dean E. McNulty, William G. Bonnette, Hongwei Qi, Liping Wang, Thau F. Ho, Anna Waszkiewicz, Lorena A. Kallal, Raman P. Nagarajan, Melissa Stern, Amy M. Quinn, Caretha L. Creasy, Dai-Shi Su, Alan P. Graves, Roland S. Annan, Sharon M. Sweitzer, Marc A. Holbert
Article
Chemistry, Medicinal
Joanne Philp, Brian G. Lawhorn, Alan P. Graves, Lisa Shewchuk, Katrina L. Rivera, Larry J. Jolivette, Dennis A. Holt, Gregory J. Gatto, Lara S. Kallander
JOURNAL OF MEDICINAL CHEMISTRY
(2018)
Article
Oncology
Heidi M. Ott, Alan P. Graves, Melissa B. Pappalardi, Michael Huddleston, Wendy S. Halsey, Ashley M. Hughes, Arthur Groy, Edward Dul, Yong Jiang, Yuchen Bai, Roland Annan, Sharad K. Verma, Steven D. Knight, Ryan G. Kruger, Dashyant Dhanak, Benjamin Schwartz, Peter J. Tummino, Caretha L. Creasy, Michael T. McCabe
MOLECULAR CANCER THERAPEUTICS
(2014)
Article
Biochemistry & Molecular Biology
Jeffrey Boehm, Roderick Davis, Claudia E. Murar, Tindy Li, Brent McCleland, Shuping Dong, Hongxing Yan, Jeffrey Kerns, Christopher J. Moody, Anthony J. Wilson, Alan P. Graves, Mary Mentzer, Hongwei Qi, John Yonchuk, Jen-Pyng Kou, Joseph Foley, Yolanda Sanchez, Patricia L. Podolin, Brian Bolognese, Catherine Booth-Genthe, Marc Galop, Lawrence Wolfe, Robin Carr, James F. Callahan
BIOORGANIC & MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Douglas W. Thomson, Daniel Poeckel, Nico Zinn, Christina Rau, Katrin Strohmer, Anne J. Wagner, Alan P. Graves, Jessica Perrin, Marcus Bantscheff, Birgit Duempelfeld, Viera Kasparcova, Joshi M. Ramanjulu, G. Scott Pesiridis, Marcel Muelbaier, Giovanna Bergamini
ACS MEDICINAL CHEMISTRY LETTERS
(2019)
Article
Chemistry, Medicinal
Guanglei Cui, Alan P. Graves, Eric S. Manas
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2020)
Article
Chemistry, Medicinal
Dai-Shi Su, Junya Qu, Mark Schulz, Chuck W. Blackledge, Hongyi Yu, Jenny Zeng, Joelle Burgess, Alexander Reif, Melissa Stern, Raman Nagarajan, Melissa Baker Pappalardi, Kristen Wong, Alan P. Graves, William Bonnette, Liping Wang, Patricia Elkins, Beth Knapp-Reed, Jeffrey D. Carson, Charles McHugh, Helai Mohammad, Ryan Kruger, Juan Luengo, Dirk A. Heerding, Caretha L. Creasy
ACS MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Medicinal
Jaclyn R. Patterson, Alan P. Graves, Patrick Stoy, Mui Cheung, Tina A. Desai, Harvey Fries, Gregory J. Gatto, Dennis A. Holt, Lisa Shewchuk, Rachel Totoritis, Liping Wang, Lara S. Kallander
Summary: A series of diarylurea inhibitors targeting the cardiac-specific kinase TNNI3K were developed with compound 47 showing promising cardioprotective effects in a mouse model, suggesting it as a favorable lead for discovering novel medicines for cardiac diseases. The structure-based design approach led to enhancements in kinase selectivity and the discovery of in vivo tool compound 47 with desirable properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Melissa B. Pappalardi, Kathryn Keenan, Mark Cockerill, Wendy A. Kellner, Alexandra Stowell, Christian Sherk, Kristen Wong, Sarath Pathuri, Jacques Briand, Michael Steidel, Philip Chapman, Arthur Groy, Ashley K. Wiseman, Charles F. McHugh, Nino Campobasso, Alan P. Graves, Emma Fairweather, Thilo Werner, Ali Raoof, Roger J. Butlin, Lourdes Rueda, John R. Horton, David T. Fosbenner, Cunyu Zhang, Jessica L. Handler, Morris Muliaditan, Makda Mebrahtu, Jon-Paul Jaworski, Dean E. McNulty, Charlotte Burt, H. Christian Eberl, Amy N. Taylor, Thau Ho, Susan Merrihew, Shawn W. Foley, Anna Rutkowska, Mei Li, Stuart P. Romeril, Kristin Goldberg, Xing Zhang, Christopher S. Kershaw, Marcus Bantscheff, Anthony J. Jurewicz, Elisabeth Minthorn, Paola Grandi, Mehul Patel, Andrew B. Benowitz, Helai P. Mohammad, Aidan G. Gilmartin, Rab K. Prinjha, Donald Ogilvie, Christopher Carpenter, Dirk Heerding, Stephen B. Baylin, Peter A. Jones, Xiaodong Cheng, Bryan W. King, Juan Luengo, Allan M. Jordan, Ian Waddell, Ryan G. Kruger, Michael T. McCabe
Summary: GSK3685032 is a potent first-in-class DNMT1-selective inhibitor that competes with the active-site loop of DNMT1 for penetration into hemi-methylated DNA. It induces robust loss of DNA methylation, transcriptional activation, and cancer cell growth inhibition in vitro. Compared with decitabine, GSK3685032 shows improved in vivo tolerability and superior tumor regression and survival in preclinical AML models.
Review
Chemistry, Medicinal
Alan P. Graves, Ian D. Wall, Colin M. Edge, James M. Woolven, Guanglei Cui, Armelle Le Gall, Xuan Hong, Kaushik Raha, Eric S. Manas
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2017)