Article
Chemistry, Medicinal
Katarzyna Bednarska-Szczepaniak, Adam Mieczkowski, Aleksandra Kierozalska, Dijana Pavlovic Saftic, Konrad Glabala, Tomasz Przygodzki, Lidia Stanczyk, Kamil Karolczak, Cezary Watala, Harsha Rao, Zhan-Guo Gao, Kenneth A. Jacobson, Zbigniew J. Lesnikowski
Summary: A series of adenosine and 2'-deoxyadenosine pairs modified with a boron cluster or phenyl group showed a general tendency to preferentially bind to the A(3) adenosine receptor. Boron cluster-modified ligands exhibited higher A(3) receptor selectivity compared to phenyl analogs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Pierre Matricon, Anh T. N. Nguyen, Duc Duy Vo, Jo-Anne Baltos, Mariama Jaiteh, Andreas Luttens, Stefanie Kampen, Arthur Christopoulos, Jan Kihlberg, Lauren Therese May, Jens Carlsson
Summary: A structure-based virtual screening approach was used to design subtype-selective ligands for A1 and A2A adenosine receptors. The study identified a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. Computational screening predicted 20 A1R selective ligands, with 7 of them exhibiting micromolar activities against A1R. Further optimization resulted in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. This study demonstrates the potential of structure-based virtual screening in guiding the discovery and optimization of subtype-selective ligands, enabling the development of safer drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Kushagra Kashyap, Pinaki Prasad Mahapatra, Shakil Ahmed, Erdem Buyukbingol, Mohammad Imran Siddiqi
Summary: In this study, a 3D convolutional neural network-based ALR2 inhibitor classification technique was developed, which successfully identified the top 10 compounds with high binding affinity. These compounds exhibited superior blood-brain barrier penetration efficiency and potential ALR2 inhibition activity, making them promising candidates for further research and optimization as anti-diabetic neuropathy drugs.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Multidisciplinary Sciences
Valeria Scardino, Juan I. Di Filippo, Claudio N. Cavasotto
Summary: A crucial component in structure-based drug discovery is high-quality three-dimensional structures of protein targets. When experimental structures are not available, homology modeling has been the preferred method. AlphaFold, an AI-based protein structure prediction method, has shown impressive accuracy. However, our evaluation using docking-based drug discovery revealed that AF models consistently performed worse compared to experimental structures. Post-modeling refinement strategies may be crucial to increase the chances of success.
Article
Biochemistry & Molecular Biology
Ji-Feng Zhao, Li-Hua Li, Xiao-Jing Guo, Hai-Xia Zhang, Chuan-Hua Ding, Wen-Shan Liu
Summary: In this study, several highly active PTP1B inhibitors were identified using high-throughput virtual screening and in vitro enzyme inhibition activity verification strategies. Baicalin was found to be a selective mixed inhibitor of PTP1B, with an IC50 value of 3.87 ± 0.45 μM. It showed dual inhibitory effect and could enhance the phosphorylation of IRS-1 in C2C12 myotube cells.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Chemistry, Medicinal
Anjali Saini, Rajiv Patel, Sobhi Gaba, Gurpreet Singh, G. D. Gupta, Vikramdeep Monga
Summary: Adenosine, an endogenous purine-based nucleoside, regulates various body functions by activating four G-protein coupled receptors. These receptors are considered drug targets for treating different diseases, but achieving target selectivity remains a challenge in drug development. Various specific radioligands-based affinity assays and other techniques have contributed to the development of selective and potent adenosine ligands.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Tijana Bojic, Milan Sencanski, Vladimir Perovic, Jelena Milicevic, Sanja Glisic
Summary: This article introduces the pharmacological research on Alzheimer's disease, focusing on the potential therapy target of the 5HT6 receptor. The study used computer simulations to screen the ZINC natural product database and found potential 5HT6 receptor antagonist candidate compounds for further evaluation.
Article
Chemistry, Physical
Swati Krishna, T. P. Krishna Murthy, G. Divyashri, Manikanta Murahari, Rohit Shukla, S. Birendra Kumar, Tiratha Raj Singh
Summary: The study designed drugs with anticancer potential by combining features of synthetic drugs and phytochemicals. Effective compounds were screened using ligand-based pharmacophore model and quantitative structure-activity relationship studies. Docking, ADMET, and molecular dynamics simulation studies confirmed the high activity and good stability of the identified compounds.
JOURNAL OF MOLECULAR LIQUIDS
(2022)
Article
Chemistry, Medicinal
Jon Kyle Awalt, Anh T. N. Nguyen, Tim J. Fyfe, Bui San Thai, Paul J. White, Arthur Christopoulos, Manuela Joerg, Lauren T. May, Peter J. Scammells
Summary: The adenosine A(1) receptor is a therapeutic target for cardioprotection during myocardial ischemia and reperfusion injury. However, clinical translation of A(1)R agonists is hindered by dose-limiting adverse effects. The bitopic agonist VCP746, consisting of an adenosine pharmacophore linked to an allosteric moiety, has shown promising results in stimulating cardioprotective A(1)R signaling effects without unwanted bradycardia. This study investigates the structure-activity relationships of VCP746 and identifies the most potent A2BR agonist to date.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Weixia Li, Baichun Hu, Haihan Liu, Jiasi Luan, Lu Chen, Shizun Wang, Liye Fan, Jian Wang
Summary: Adenosine A(1) receptor and adenosine A(2A) receptor play different roles in regulating arteriolar pressure and urine flow as well as relieving neurodegenerative disorders. Understanding their selective inhibition mechanisms is crucial for the rational design of selective inhibitors.
NEW JOURNAL OF CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Jonathan G. L. Mullins
Summary: This article reviews the exciting progress made in the development of in silico platforms and methods for drug repurposing over the past decade, highlighting their broad value in research. Recent advancements in molecular docking, machine learning, and deep learning have improved the accuracy of drug repurposing efforts. The integration of molecular mechanisms, molecular pathway data, and disease networks has expanded the scope of repurposing opportunities. Artificial intelligence plays a significant role in advancing integrated science, but challenges remain in successfully integrating new developments into useful platforms.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Article
Chemistry, Medicinal
Kristina Puls, Aina-Leonor Olive-Marti, Szymon Pach, Birgit Pinter, Filippo Erli, Gerhard Wolber, Mariana Spetea
Summary: In this study, the new opioid ligand Compound A was characterized as a kappa-opioid receptor (KOR) antagonist both in vitro and in vivo. It demonstrated moderate binding affinity to the human KOR and selective binding profile compared to the mu-opioid receptor (MOR) and delta-opioid receptor (DOR). In addition, Compound A effectively reversed the antinociceptive effects of a KOR agonist in mice. Computer simulations revealed the structural determinants responsible for its selective binding to the KOR. This new compound holds promise for the development of potential therapeutics.
Article
Chemistry, Multidisciplinary
Shidi Xu, Xiaoling Huang, Yufeng An, Xinya Lv, Shan Xu, Linxiao Wang, Wufu Zhu
Summary: This study successfully discovered a novel fourth-generation EGFR inhibitor with a new scaffold using a drug discovery strategy. The optimized compound, T001-10026247, showed excellent inhibitory activity against various lung cancer cells and demonstrated potential EGFR inhibition in in vitro and in vivo evaluations.
NEW JOURNAL OF CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Kanpong Boonthaworn, Kowit Hengphasatporn, Yasuteru Shigeta, Warinthorn Chavasiri, Thanyada Rungrotmongkol, Puey Ounjai
Summary: Yellow head virus (YHV) is a major pathogen in prawn cultivation that can cause collapses in aquaculture industries. Despite efforts to find preventive and therapeutic approaches, there is still no effective therapy available in the market.
Article
Biochemical Research Methods
Balaji Wamanrao Matore, Purusottam Banjare, Jagadish Singh, Partha Pratim Roy
Summary: Designing selective drug candidates for structurally similar targets is a challenging task. This study aimed to explore the selectivity modeling of pyridine and pyrimidine scaffold towards highly homologous targets CYP11B1 and CYP11B2 enzymes using computational methods. Molecular docking and QSAR analysis revealed the importance of structural features and functional groups for selectivity and highlighted the differentiating amino acid residues for ligand selectivity. These findings will be useful for designing selective CYP11B1/CYP11B2 inhibitors.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Biochemistry & Molecular Biology
Kiran S. Toti, Ryan G. Campbell, Hobin Lee, Veronica Salmaso, R. Rama Suresh, Zhan-Guo Gao, Kenneth A. Jacobson
Summary: Adenosine receptor (AR) ligands are being developed for the treatment of metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. Fluorescent antagonist ligands were synthesized and screened for their affinities and selectivity towards different AR subtypes, showing potential as live cell or in vivo imaging tools and/or therapies.
PURINERGIC SIGNALLING
(2023)
Book Review
Chemistry, Medicinal
Kenneth A. Jacobson
Article
Chemistry, Medicinal
Lukas Heyder, Phil M. M. Hochban, Corey Taylor, Florent Chevillard, Christof Siefker, Christian Iking, Hannes Borchardt, Achim Aigner, Gerhard Klebe, Andreas Heine, Peter Kolb, Wibke E. Diederich
Summary: In this study, fragment-sized hits binding to Pim-1 kinase were optimized using a combination of computational, synthetic, and crystallographic expertise. The resulting potent ligands target rarely-targeted regions of Pim-1 kinase with affinities in the nanomolar range. The combination of computational and experimental approaches successfully developed a novel molecular scaffold for inhibition of Pim-1 kinase, targeting specific surface regions that have been less frequently investigated.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Neurosciences
Kenneth A. Jacobson, Balaram Pradhan, Zhiwei Wen, Asmita Pramanik
Summary: The discovery and clinical implementation of adenosine, P2Y and P2X receptor modulators have advanced significantly in the past 50 years. Although previous clinical trials of selective ligands have not been successful, there is now a renewed focus on new disease conditions and the development of more selective compounds, as well as the elucidation of new receptor and enzyme structures.
Article
Chemistry, Medicinal
Jung-Eun Park, Hobin Lee, Paola Oliva, Klara Kirsch, Bora Kim, Jong Il Ahn, Celeste N. Alverez, Snehal Gaikwad, Kristopher W. Krausz, Robert O'Connor, Ganesha Rai, Anton Simeonov, Beverly A. Mock, Frank J. Gonzalez, Kyung S. Lee, Kenneth A. Jacobson
Summary: Polo-like kinase 1 (Plk1) is an attractive target for anticancer drug discovery due to its widely upregulated activity in various human cancers. In addition to the kinase domain, the C-terminal noncatalytic polo-box domain (PBD) has emerged as an alternative target for developing inhibitors. Triazoloquinazolinone-derived inhibitors effectively block Plk1 with improved affinity and drug-like properties. Further derivatization is needed to improve the stability of these inhibitors for the development of therapeutics against Plk1-addicted cancers.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Qasim Shah, Zahid Hussain, Bilal Ahmad Khan, Kenneth A. Jacobson, Jamshed Iqbal
Summary: The study investigates the potency of P2X7 receptor antagonists and their relationship with cancer, revealing five compounds with strong selective inhibitory effects. These compounds exhibit varying cell viability and induction of apoptosis in transfected and non-transfected cell lines.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Maggie M. Calkins, Marko S. Ivancich, Hailey A. Bock, Ryan G. Campbell, Sarah A. Lewicki, Eric Chen, Zhan-Guo Gao, John D. Mccorvy, Kenneth A. Jacobson
Summary: Derivatives of (N)-Methanocarba adenosine were modified to target 5-HT2B serotonin receptors as antagonists, showing affinity enhancement with the bicyclic ring system. Compound 43 (MRS7925) exhibited potential for anti-fibrotic therapy due to its affinity and moderate 5-HT2BR binding selectivity. The compounds also demonstrated dual action as 5-HT2B antagonists and A(1)AR agonists.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Katarina Mihajlovic, Marija Adzic Bukvic, Milorad Dragic, Mirko Scortichini, Kenneth A. Jacobson, Nadezda Nedeljkovic
Summary: In this in vitro study, three novel cytosine-derived alpha,beta-methylene diphosphonates (MRS4598, MRS4552, and MRS4602) were tested for their potency in inhibiting CD73 activity and attenuating reactive astrocyte phenotype. The results showed that all compounds exhibited concentration-dependent inhibition of CD73 activity with high inhibitory potency and binding capacity. Among them, MRS4598 was the most effective in inhibiting CD73 activity and inducing reactive astrocyte phenotype inhibition, making it a promising tool for the treatment of neurodegeneration and neuroinflammation.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Zhiwei Wen, Asmita Pramanik, Sarah A. Lewicki, Young-Hwan Jung, Zhan-Guo Gao, John C. R. Randle, Chunxia Cronin, Zhoumou Chen, Luigino A. Giancotti, Gregory S. Whitehead, Bruce T. Liang, Sylvie Breton, Daniela Salvemini, Donald N. Cook, Kenneth A. Jacobson
Summary: P2Y(14) receptor is activated by extracellular UDP-glucose, promoting inflammation in various tissues. Selective P2Y(14)R antagonists could be useful for inflammatory and metabolic diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Merlin Bresinsky, Aida Shahraki, Peter Kolb, Steffen Pockes, Hannes Schihada
Summary: In this study, a signaling pathway-independent readout of compound-GPR3 interaction was developed, providing new cues for the pharmacological manipulation of GPR3 activity. This has significant implications for the future development of drugs targeting these pharmacologically attractive oGPCRs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Hai-Jun Zhang, Michal Ociepa, Molhm Nassir, Bin Zheng, Sarah A. Lewicki, Veronica Salmaso, Helay Baburi, Jessica Nagel, Salahuddin Mirza, Haneen Al-Hroub, Beatriz Bueschbell, Olga Perzanowska, Ziqin Lin, Michael A. Schmidt, Martin D. Eastgate, Kenneth A. Jacobson, Christa E. Mueller, Joanna Kowalska, Jacek Jemielity, Phil S. Baran
Summary: Nucleoside diphosphates and triphosphates have a profound impact on biochemistry, but their usage as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hindered by their rapid metabolism in the body. This study demonstrates the development of a modular, reagent-based platform that allows the stereocontrolled and scalable synthesis of pure stereoisomers of nucleoside thioisosteres, which can have significant effects on ligand-receptor interactions.
Article
Chemistry, Medicinal
Eline Pottie, R. Rama Suresh, Kenneth A. Jacobson, Christophe P. Stove
Summary: This study aimed to explore inverse agonism at A(3)AR using two engineered cell lines and NanoBiT technology. The previously established inverse agonist PSB-10 showed inverse agonism in one assay but not in another. Further experiments confirmed the specificity and reversibility of this observation. Evaluation of presumed neutral antagonists revealed their concentration-dependent inverse agonism in the A(3)AR-βarr2 recruitment assay.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Dilip K. Tosh, Courtney L. Fisher, Veronica Salmaso, Tina C. Wan, Ryan G. Campbell, Eric Chen, Zhan-Guo Gao, John A. Auchampach, Kenneth A. Jacobson
Summary: (N)-Methanocarba adenosine derivatives were modified to form macrocyclic A(3) adenosine receptor agonists. These macrocycles retained affinity and had a spatially proximal orientation on the receptor. C2-Arylethynyl-linked macrocycle 19 showed higher selectivity for A(3) adenosine receptor compared to 2-ether-linked macrocycle 12.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Niklas Rosier, Denise Moennich, Martin Nagl, Hannes Schihada, Alexei Sirbu, Nergis Konar, Irene Reyes-Resina, Gemma Navarro, Rafael Franco, Peter Kolb, Paolo Annibale, Steffen Pockes
Summary: Dopamine D-1-like receptors are the most abundant type of dopamine receptors in the central nervous system. The synthesis of new fluorescent ligands derived from D1R antagonist SCH-23390 was described, which can be used as tools for the visualization of D-1-like receptors. The high-affinity ligand UR-NR435 (25) showed excellent selectivity towards D-1-like receptors and proved to be a neutral antagonist in binding studies. This fluorescent ligand is a useful tool for studying native D-1 receptors in various experimental setups.
Article
Biochemistry & Molecular Biology
Martin Nagl, Denise Moennich, Niklas Rosier, Hannes Schihada, Alexei Sirbu, Nergis Konar, Irene Reyes-Resina, Gemma Navarro, Rafael Franco, Peter Kolb, Paolo Annibale, Steffen Pockes
Summary: This study describes the synthesis of a set of new fluorescent ligands for visualization of dopamine D-2-like receptors. The ligand UR-MN212 (20) showed high affinity for D-2-like receptors and moderate selectivity towards D-1-like receptors. It displayed rapid association with D2longR and can be used for fluorescence microscopy studies. The ligand's binding affinity was determined in a single-digit nanomolar range, consistent with radioligand binding data.