Article
Biochemistry & Molecular Biology
Norburhanuddin Johari Zaidi, Adib Afandi Abdullah, Choon Han Heh, Chun-Hung Lin, Rozana Othman, Abdullah Al Hadi Ahmad Fuaad
Summary: The global incidence of dengue infection is rising, but no therapeutic treatment is available. This study used computational methods to identify potential dengue virus inhibitory peptides, and the in vitro results validated the computational findings, highlighting the value of computational research in the lead optimization of antiviral peptides.
Article
Chemistry, Medicinal
Timo Heinrich, Carl Peterson, Richard Schneider, Sakshi Garg, Daniel Schwarz, Jakub Gunera, Anita Seshire, Lisa Koetzner, Sarah Schlesiger, Djordje Musil, Heike Schilke, Benjamin Doerfel, Patrizia Diehl, Pia Boepple, Ana R. Lemos, Pedro M. F. Sousa, Filipe Freire, Tiago M. Bandeiras, Emma Carswell, Nicholas Pearson, Sameer Sirohi, Mollie Hooker, Elisabeth Trivier, Rebecca Broome, Alexander Balsiger, Abigail Crowden, Christian Dillon, Dirk Wienke
Summary: The dysregulated Hippo pathway and hyperactivity of the YAP/TAZ-TEAD transcriptional complexes are associated with diseases like cancer. This study describes the discovery and optimization of a P-site binding fragment to target the TEAD transcription factors. The optimized in vivo tool, MSC-4106, exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Semih Yagci, Mahmut Gozelle, Selen Gozde Kaya, Yesim Ozkan, Ahmet Bugra Aksel, Filiz Bakar-Ates, Yasemin Dundar, Gokcen Eren
Summary: The study focused on hit-to-lead optimization of a potential SIRT1/2 inhibitor, resulting in improved selectivity for SIRT1 and SIRT2 inhibition. The structural modifications also influenced the cytotoxicity of the compounds against MCF-7 human breast cancer cell line, indicating the impact of SIRT1/2 inhibition on cancer cell viability.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Koon Mook Kang, Yejin Jang, Sang Soo Lee, Mi Sun Jin, Chang-Duk Jun, Meehyein Kim, Yong-Chul Kim
Summary: This study reports the development of novel SARS-CoV-2 Mpro inhibitors derived from carmofur and their optimization through experimental and simulation methods. Two compounds with strong inhibitory activity were identified, and their antiviral effects against SARS-CoV-2 were confirmed, suggesting their potential as lead compounds for the development of anti-SARS-CoV-2 agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dean G. Brown
Summary: An analysis of 156 published clinical candidates from the Journal of Medicinal Chemistry between 2018 and 2021 revealed that the most frequently employed lead generation strategies leading to drug candidates were known compounds (59%) and random screening approaches (21%). Other approaches included directed screening, fragment screening, DNA-encoded library screening (DEL), and virtual screening. Similarity analysis based on Tanimoto-MCS showed that most clinical candidates were distant from their original hits, but shared a key pharmacophore. The frequency of oxygen, nitrogen, fluorine, chlorine, and sulfur incorporation in clinical candidates was also examined. The study also provided insights into the changes that occur from hit-to-clinical candidate based on the most similar and least similar hit-to-clinical pairs from random screening.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Xin Wen, Xinyuan Wu, Rui Jin, Xiaojie Lu
Summary: It is well known that heterocyclic compounds play a key role in improving drug activity, target selectivity, physicochemical properties as well as reducing toxicity. In this review, we summarized the representative heterocyclic structures involved in hit compounds which were obtained from DNA-encoded library from 2013 to 2021. The state of the art in heterocycle-based DEL synthesis and hit-to-lead optimization are highlighted in some examples. We hope that more and more novel heterocycle-based DEL toolboxes and in-depth pharmaceutical research on these lead compounds can be developed to accelerate the discovery of new drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
John R. Cashman, Daniel Ryan, Wesley L. McKeithan, Karl Okolotowicz, Jorge Gomez-Galeno, Mark Johnson, Kevin J. Sampson, Robert S. Kass, Arash Pezhouman, Hrayr S. Karagueuzian, Mark Mercola
Summary: Ventricular cardiac arrhythmia can occur in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel SCN5A mutations. Mexiletine can inhibit I-NaL and shorten the QT interval, but can also prolong the cardiac action potential at therapeutic doses.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Gilda Padalino, Nelly El-Sakkary, Lawrence J. Liu, Chenxi Liu, Danielle S. G. Harte, Rachel E. Barnes, Edward Sayers, Josephine Forde-Thomas, Helen Whiteland, Marcella Bassetto, Salvatore Ferla, George Johnson, Arwyn T. Jones, Conor R. Caffrey, Iain Chalmers, Andrea Brancale, Karl F. Hoffmann
Summary: Recent research has identified a promising anti-schistosomal scaffold in the quinoxaline core, which has shown improved activity and selectivity through chemical optimization. This could potentially serve as an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Thibault Joseph William Jacques Dit Lapierre, Mariza Gabriela Faleiro de Moura Lodi Cruz, Nicolas Peterson Ferreira Brito, Daniela de Melo Resende, Felipe de Oliveira Souza, Eduardo Jorge Pilau, Meryck Felipe Brito da Silva, Bruno Junior Neves, Silvane Maria Fonseca Murta, Celso de Oliveira Rezende Junior
Summary: An early hit-to-lead optimization study was performed on a novel pyrazinylpiperazine series against L. infantum and L. braziliensis. The study focused on the benzoyl fragment of a hit compound (4), and deletion of the meta-Cl led to the synthesis of a para-hydroxyl derivative (12). Further optimization involving disubstituted benzoyl fragments and the hydroxyl substituent of (12) resulted in the identification of an ortho, meta-dihydroxyl derivative (46) as an early lead compound with increased anti-leishmanial potency. In silico ADMET predictions revealed satisfactory profiles for these compounds, indicating potential for further lead optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Elli-Anna Stylianaki, Christiana Magkrioti, Eleni M. Ladopoulou, Konstantinos D. Papavasileiou, Panagiotis Lagarias, Georgia Melagraki, Martina Samiotaki, George Panayotou, Skarlatos G. Dedos, Antreas Afantitis, Vassilis Aidinis, Alexios N. Matralis
Summary: Robust experimental evidence has shown the importance of the ATX/LPA axis in chronic inflammatory conditions, fibroproliferative diseases, and cancer. Various ATX inhibitors have been discovered, with the first-in-class inhibitor currently in advanced clinical trials for idiopathic pulmonary fibrosis. The mode of inhibition and binding mechanism of these inhibitors to ATX have been studied.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Grigorii Andrianov, Wern Juin Gabriel Ong, Ilya Serebriiskii, John Karanicolas
Summary: The computational strategy described focuses on identifying kinase inhibitor analogues with improved potency using enumerated libraries generated from commercially available replacements for building blocks of the parent inhibitor. By considering alternate approaches, top-scoring compounds can be identified without the need for explicit virtual screening. Pairwise approximation allows for interaction energies to be assigned to compounds in the library, facilitating energy minimizations and enabling the rapid assembly and screening of large libraries for hit-to-lead optimization.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Medicinal
Louise Walsh, Daniel A. Erlanson, Iwan J. P. de Esch, Wolfgang Jahnke, Andrew Woodhead, Ella Wren
Summary: This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in 2021. It provides a tabulated summary of relevant articles and discusses target class, screening methods, and ligand efficiency for both 2021 examples and combined examples from 2015 to 2021. Additionally, it summarizes trends and new developments in the field, focusing on the use of structural information in fragment-based drug discovery.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Yoshifumi Kusumoto, Kyohei Hayashi, Soichiro Sato, Toru Yamada, Iori Kozono, Zenzaburo Nakata, Naoya Asada, Shungo Mitsuki, Ayahisa Watanabe, Chiaki Wakasa-Morimoto, Kentaro Uemura, Shuhei Arita, Shinobu Miki, Tohru Mizutare, Hidenori Mikamiyama
Summary: In this study, a novel HIV-1 protease inhibitor with potent antiviral activity and oral bioavailability was discovered using a structure-based drug design approach via X-ray crystal structure analysis and improved metabolic stability.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Celso de Oliveira Rezende Jr, Pablo David Grigol Martinez, Rafael Augusto Alves Ferreira, Paul John Koovits, Bruna Miranda Soares, Leonardo L. G. Ferreira, Simone Michelan-Duarte, Rafael Consolin Chelucci, Adriano D. Andricopulo, An Matheeussen, Natascha Van Pelt, Guy Caljon, Louis Maes, Simon Campbell, Jadel M. Kratz, Charles E. Mowbray, Luiz Carlos Dias
Summary: This study describes the optimization of a 2-aminobenzimidazole hit for the treatment of Chagas disease, focusing on improving potency, selectivity, stability, and lipophilicity. Although the properties of the initial hits were improved, their low solubility and cytotoxicity prevented further efficacy studies in a mouse model of Chagas disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Nicole McNamara, Eleanor Saunders, Swapna Varghese, Rebecca Zheng, Kaylene Simpson, Devika M. Varma, Monica M. Johnson, M. Shamim Hasan Zahid, Eric M. Bachelder, Kristy M. Ainslie, Joo Hwan No, Dahae Koh, David Shum, Nirmal Das, Binita Patra, Jayasree Roy, Arindam Talukdar, Dipyman Ganguly, Malcolm McConville, Jonathan Baell
Summary: In this study, the structure-activity relationship of a novel hit compound was explored. The compound showed improved potency with low cytotoxicity against human cells, indicating its potential as a treatment for visceral leishmaniasis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)