Review
Biochemistry & Molecular Biology
Math P. Cuajungco, Maria Soledad Ramirez, Marcelo E. Tolmasky
Summary: This article discusses the influence of zinc on various mechanisms of bacterial proliferation and its synergistic action as an antimicrobial element. It also touches upon the importance of zinc among eukaryotic cells and how it modulates their survival and death.
Article
Chemistry, Medicinal
Iwan J. P. de Esch, Daniel A. Erlanson, Wolfgang Jahnke, Christopher N. Johnson, Louise Walsh
Summary: The review summarizes successful fragment-to-lead studies published in 2020 and discusses trends and best practices in fragment libraries, target proteins, screening technologies, hit-optimization strategies, and properties of hit fragments and leads. Trends and innovations identified in the review promise to further increase the success of FBDD by developing novel screening fragments, improving screening technologies, using computer-aided design and virtual screening, and combining FBDD with other drug-discovery technologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Engineering, Environmental
Gauthier J. -P. Deblonde, Keith Morrison, Joseph A. Mattocks, Joseph A. Cotruvo, Mavrik Zavarin, Annie B. Kersting
Summary: Minor actinides play a significant role in the radiotoxicity of nuclear fuels and radioactive wastes. Understanding their interactions with natural chelators and minerals is crucial for evaluating their transport behavior in the environment.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Article
Chemistry, Medicinal
Youhai Tan, Lingxue Dai, Weifeng Huang, Yinfeng Guo, Shuangjia Zheng, Jinping Lei, Yuedong Yang, Hongming Chen
Summary: In this study, a novel framework called DRlinker was proposed to control fragment linking for generating candidate compounds with specified attributes using reinforcement learning. The method has been proven effective for various tasks, including controlling linker length and log P, optimizing predicted bioactivity of compounds, and handling multiple objectives.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Youhai Tan, Lingxue Dai, Weifeng Huang, Yinfeng Guo, Shuangjia Zheng, Jinping Lei, Hongming Chen, Yuedong Yang
Summary: A novel framework called DRlinker was proposed in this study to control fragment linking and generate compounds with specified attributes through reinforcement learning. The method has been demonstrated to be effective in various tasks, including controlling linker length and log P, optimizing predicted bioactivity of compounds, and achieving various multiobjective tasks.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Isaline F. S. F. Castan, Jessica S. Graham, Catherine L. A. Salvini, Harriet A. Stanway-Gordon, Michael J. Waring
Summary: DNA-encoded libraries (DELs) have become an established technology for finding ligands for protein targets and have led to hit compounds across diverse protein classes. However, the range of reactions and monomers utilized is relatively limited and the hit compounds are often higher in molecular weight than ideal. Considerations for future library designs include chemical diversity and lead-like properties.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Harrison Green, David R. Koes, Jacob D. Durrant
Summary: Machine learning has been increasingly applied in the field of computer-aided drug discovery, showing notable advances in binding-affinity prediction, virtual screening, and QSAR. A deep convolutional neural network was used to predict appropriate fragments based on the structure of a receptor/ligand complex, with an efficiency of about 58% in selecting correct fragments from known ligands. The trained DeepFrag model and its associated software have been released under the Apache License, Version 2.0.
Review
Infectious Diseases
Monika I. Konaklieva, Balbina J. Plotkin
Summary: Fragment-based lead discovery (FBLD) is an effective approach used to develop ligands as modulators of disease targets. This method focuses on identifying interactions between low-molecular weight compounds and their potential targets, with low affinity interactions. The review focuses on the past five years of fragment-based drug discovery strategies for antimicrobial drug development.
Article
Pharmacology & Pharmacy
Mengshi Li, Nicholas J. Baumhover, Dijie Liu, Brianna S. Cagle, Frederic Boschetti, Guillaume Paulin, Dongyoul Lee, Zhiming Dai, Ephraim R. Obot, Brenna M. Marks, Ibrahim Okeil, Edwin A. Sagastume, Moustafa Gabr, F. Christopher Pigge, Frances L. Johnson, Michael K. Schultz
Summary: A cyclen-based Pb-specific chelator (PSC) conjugated to tyr(3)-octreotide via a PEG(2) linker (PSC-PEG-T) was developed to target SSTR2. Efficient radiolabeling of purified Pb-212 and Bi-212 as well as mixed Pb-212 and Bi-212 in PSC-PEG-T was observed. Stable radiometal complexes were formed in saline and serum, and in vivo studies demonstrated the potential of [Pb-203]Pb-PSC-PEG-T and [Pb-212]Pb-PSC-PEG-T for tumor imaging.
Article
Chemistry, Multidisciplinary
Yibo Li, Jianfeng Pei, Luhua Lai
Summary: DeepLigBuilder is a novel deep learning-based method for de novo drug design that generates 3D molecular structures in the binding sites of target proteins. By utilizing L-Net model and Monte Carlo tree search for structure-based de novo drug design tasks, it provides new approaches and ideas for drug design.
Article
Chemistry, Medicinal
Jieyu Jin, Dong Wang, Guqin Shi, Jingxiao Bao, Jike Wang, Haotian Zhang, Peichen Pan, Dan Li, Xiaojun Yao, Huanxiang Liu, Tingjun Hou, Yu Kang
Summary: Recently, deep generative models, such as FFLOM, have shown promise in fragment-based drug design by generating molecules with desired properties. FFLOM achieves state-of-the-art performance in terms of validity, uniqueness, novelty, and recovery of generated molecules. It also demonstrates excellent potential in practical scenarios including fragment linking, PROTAC design, R-group growing, and R-group optimization, generating molecules with novel fragments and higher binding affinity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Lewis D. Turner, Chi H. Trinh, Ryan A. Hubball, Kyle M. Orritt, Chi-Chuan Lin, Julie E. Burns, Margaret A. Knowles, Colin W. G. Fishwick
Summary: This study describes a structure-guided approach to design a selective FGFR2 inhibitor, resulting in a nanomolar potency inhibitor with moderate selectivity for FGFR2. The study reveals that inhibitor-specific morphological differences may play a crucial role in selectivity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Pearly Shuyi Ng, Klement Foo, Sandra Sim, Gang Wang, Chuhui Huang, Li Hong Tan, Anders Poulsen, Boping Liu, Doris Hui Ying Tee, Nur Huda Binte Ahmad, Sifang Wang, Zhiyuan Ke, May Ann Lee, Zekui P. Kwek, Joma Joy, Jothi Anantharajan, Nithya Baburajendran, Vishal Pendharkar, Vithya Manoharan, Susmitha Vuddagiri, Kanda Sangthongpitag, Jeffrey Hill, Thomas H. Keller, Alvin W. Hung
Summary: This study identified a new indazole-based AXL inhibitor through a fragment-based lead discovery approach, providing a suitable starting point for further optimization efforts.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, Ross J. Taylor, Rosaria Russo, Goncalo J. L. Bernardes, Stefano Ricagno, Judith Frydman, Michele Vendruscolo, Pietro Sormanni
Summary: De novo design methods enable the rapid generation of lead antibodies binding to preselected epitopes without in vitro affinity maturation, and high-resolution input antigen structure is not required.
Article
Multidisciplinary Sciences
Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, Ross J. Taylor, Rosaria Russo, Goncalo J. L. Bernardes, Stefano Ricagno, Judith Frydman, Michele Vendruscolo, Pietro Sormanni
Summary: The method describes a fragment-based approach to design antibody binding loops and graft them onto antibody scaffolds, providing a starting point for rapidly generating lead antibodies binding to preselected epitopes without the need for a high-resolution input antigen structure.
Article
Chemistry, Multidisciplinary
R. Eric Sikma, Seth M. Cohen
Summary: This study reports the rational design and synthesis of three-dimensional metal-organic frameworks (MOFs) with Pd-0 and Pt-0 nodes using tetratopic phosphine ligands. Five new MOFs have been synthesized by varying the phosphine ligands and metal precursors, and they are the first examples of phosphine-metal bonded MOFs. These MOFs exhibit solid-state luminescence with significantly red-shifted emission maxima compared to Pd(PPh3)(4). Additionally, a Rh-I low-valent coordination solid based on the same linker design is reported, which displays solid-state luminescence not observed in the molecular analogue.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Inorganic & Nuclear
Jie Zhu, Laura Samperisi, Mark Kalaj, Jerika A. Chiong, Jake B. Bailey, Zhiyin Zhang, Chung-Jui Yu, R. Eric Sikma, Xiaodong Zou, Seth M. Cohen, Zhehao Huang, F. Akif Tezcan
Summary: We report the synthesis and characterization of a new series of permanently porous, three-dimensional metal-organic frameworks (MOFs), M-HAF-2 (M = Fe, Ga, or In), constructed from tetratopic, hydroxamate-based, chelating linkers. The structure of M-HAF-2 was determined by three-dimensional electron diffraction (3D ED), revealing a unique interpenetrated hcb-a net topology. This material shows high thermal and chemical stability and can be used for ionic separations.
DALTON TRANSACTIONS
(2022)
Article
Chemistry, Multidisciplinary
Jessica C. Moreton, Jin Xiang Low, Katrina C. Penticoff, Seth M. Cohen, Lauren Benz
Summary: X-ray photoelectron spectroscopy can be used to compare the relative concentrations of exchanged ligands at the surface and interior regions of MOF particles, revealing the ligand distribution during PSE process. The study also found differences in surface chemistry between the PSE product and the directly synthesized product.
Article
Chemistry, Multidisciplinary
Moritz K. Jackl, Hyeonglim Seo, Johannes Karges, Mark Kalaj, Seth M. Cohen
Summary: Metalloenzyme inhibitors typically require a metal-binding pharmacophore (MBP), but MBPs can have limitations. In this study, a total of 27 salicylate metal-binding isosteres (MBIs) were synthesized as replacements for the carboxylic and hydroxyl group of the salicylic acid MBP. These salicylate MBIs were characterized for their metal-binding features, physicochemical properties, and biological activity. The results showed that salicylate MBIs can have attractive physicochemical properties and maintain or improve enzyme inhibition and selectivity.
Article
Chemistry, Multidisciplinary
Kyle Barcus, Po-An Lin, Yilong Zhou, Gaurav Arya, Seth M. Cohen
Summary: Polymer-grafted metal-organic frameworks (MOFs) combine the properties of MOFs and polymers into a matrix-free composite material. The choice of polymer affects the physical properties of the monolayers, and poly(methyl acrylate) is more suitable for producing robust, flexible monolayers. Molecular dynamics simulations provide insights into the orientation and ordering of MOFs in the monolayers, and the relationship between molecular weight and graft density of the polymer brush can be used for further optimization of mechanical strength, MOF weight fraction, and processability.
Article
Chemistry, Multidisciplinary
Hyeonglim Seo, Alysia J. J. Kohlbrand, Ryjul W. W. Stokes, Jeewon Chung, Seth M. M. Cohen
Summary: Thioamides, thioureas, and thiocarbamates are introduced as stable metal-binding pharmacophores for use in metalloenzyme fragment-based drug discovery. Studies show that these molecules can act as ligands for Zn(ii)-dependent metalloenzymes including human carbonic anhydrase II and matrix metalloproteinase-2.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Conor B. O'Herin, Yuta W. Moriuchi, Troy A. Bemis, Alysia J. Kohlbrand, Michael D. Burkart, Seth M. Cohen
Summary: Human carbonic anhydrase II (hCAII) is a vital metalloenzyme in the human body, and its inhibitors have clinical applications in treating various diseases. This study developed degrader candidates targeting hCAII, which showed promising potential in inducing the degradation of hCAII. Optimization of the candidates resulted in a highly potent degrader with sustained depletion of hCAII. Mechanistic studies indicated that this optimized degrader functions similarly to previously reported CRBN-recruiting degraders.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Johannes Karges, Miriam A. Giardini, Olivier Blacque, Brendon Woodworth, Jair L. Siqueira-Neto, Seth M. Cohen
Summary: Functionalized Re(i) tricarbonyl complexes were synthesized and found to inhibit the activity of the SARS-CoV-2 main protease, presenting a potential antiviral strategy.
Letter
Chemistry, Medicinal
Ryjul W. Stokes, Alysia J. Kohlbrand, Hyeonglim Seo, Banumathi Sankaran, Johannes Karges, Seth M. Cohen
Summary: In this study, various metal-binding isosteres (MBIs) were examined to modulate the activity of the RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease. The inhibitory ability of MBIs against PAN was evaluated using a FRET-based enzymatic assay, and their binding mode in PAN was determined using X-ray crystallography.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Samuel E. Griffin, Grant P. Domecus, Clarissa E. Flores, R. Eric Sikma, Lauren Benz, Seth M. Cohen
Summary: Low-valent metal-organic frameworks (LVMOFs) and related materials have potential applications in heterogeneous catalysis, but no catalytic activity has been observed in the reported LVMOFs. In this study, a low-valent metal-organic material constructed from phosphine linkers and Ir-I nodes is reported. This material, similar to Vaska's complex, can reversibly bind O-2 and catalyze the reductive formation of enamines from amides.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Medicinal
Johannes Karges, Seth M. Cohen
Summary: Interest in covalent enzyme inhibitors as therapeutic agents has recently increased. In this article, the use of small, modular ReV complexes as inorganic cysteine-targeting warheads is described. These metal complexes were found to react rapidly and selectively with cysteine residues. The utility of these ReV complexes was demonstrated by their inhibition of SARS-CoV-2-associated cysteine proteases and human enzymes cathepsin B and L through the formation of adducts.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Austin Wang, Kyle Barcus, Seth M. Cohen
Summary: The surface chemistry of three MOFs, UiO-66, MIL-88B-NH2, and ZIF-8, was investigated using dye-displacement experiments. Ligand affinity on the MOF surface was found to be dependent on the metal-ligand composition. This work provides important insights for the modulation, modification, and manipulation of MOFs.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Physical
Prantik Mondal, Zhaoxi Zheng, Klaus Schmidt-Rohr, Seth M. Cohen
Summary: Postsynthetic modification (PSM) is an important tool for functionalizing metal-organic frameworks (MOFs). However, the availability of organic linkers with readily modified functional groups remains a challenge. In this study, a benzene dicarboxylic acid with azidomethyl groups was synthesized and introduced into two different MOF structures. The pendant alkyl azide groups in these MOFs were amenable to PSM via click reactions. Furthermore, the pore size restriction in one of the MOFs could be overcome by using a mixed ligand approach. Importantly, the azidomethyl groups could be reduced to primary benzylic amines, maintaining the crystallinity and porosity of the MOF.
CHEMISTRY OF MATERIALS
(2023)
Article
Chemistry, Multidisciplinary
Prantik Mondal, Seth M. Cohen
Summary: Mixed-matrix membranes (MMMs) with self-healing ability were prepared using Zr(iv)-based MOFs. These MMMs demonstrated good mechanical strength and could undergo repeated self-healing without a loss in catalytic activity towards a chemical warfare agent (CWA) simulant. The reversible hydrolysis of boronic-ester conjugates played a key role in the self-healing process.
Correction
Chemistry, Multidisciplinary
Christine N. Morrison, Kathleen E. Prosser, Ryjul W. Stokes, Anna Cordes, Nils Metzler-Nolte, Seth M. Cohen
Summary: The study introduces a novel approach using metallofragments as 3D scaffolds for fragment-based drug discovery. This method has great potential in the field of medicinal chemistry and provides a new direction for drug development.
