Article
Chemistry, Medicinal
Ziwen Zhang, Shi-Long Zhang, Chengyao Wu, Huan-Huan Li, Liang Zha, Jingbo Shi, Xinhua Liu, Hua-Li Qin, Wenjian Tang
Summary: SuFEx click chemistry has been demonstrated as a powerful method for the rapid synthesis of sulfonamide inhibitors for high-throughput testing of cholinesterase activity. By applying this methodology, a diverse library of sulfonamides was synthesized and directly screened to yield drug-like inhibitors with significantly enhanced potency. The improved molecule J8-A34 showed effectiveness in improving cognitive function in a mouse model. This study highlights the potential of SuFEx click chemistry for accelerating the development of biological probes and drug candidates.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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.
Review
Cell Biology
Helen Power, Peter Valtchev, Fariba Dehghani, Aaron Schindeler
Summary: This article discusses the classification of senolytic drugs and methods for screening new drugs. Researchers have discovered a range of senolytic drugs and introduce their different categories and mechanisms of action. The article also highlights the need for further research into drug targets and mechanisms, as well as rigorous evaluation in pre-clinical models and human trials.
Review
Chemistry, Medicinal
Bhawna Chopra, Ashwani Kumar Dhingra
Summary: Natural products have been used in folklore for centuries for treating various ailments, with plant-derived products recognized as a source of therapeutic agents and structural diversity. After small modifications, natural molecules can offer better pharmacological potential as new molecular entities.
PHYTOTHERAPY RESEARCH
(2021)
Review
Pharmacology & Pharmacy
Chuanfeng Liu, Lide Hu, Guanyu Dong, Ying Zhang, Edeildo Ferreira da Silva-Junior, Xinyong Liu, Luis Menendez- Arias, Peng Zhan
Summary: Influenza is a respiratory infection caused by influenza viruses, resulting in millions of severe cases and deaths each year. The frequent mutations and resistance to antiviral drugs make it necessary to develop efficient drugs against different strains of influenza. This review summarizes strategies for discovering and developing antiviral agents targeting multiple strains of influenza, including drug design based on structure, mechanism, multivalent interaction, and repurposing.
ACTA PHARMACEUTICA SINICA B
(2023)
Review
Biochemistry & Molecular Biology
Zhihong Xu, Barrett Eichler, Eytan A. A. Klausner, Jetty Duffy-Matzner, Weifan Zheng
Summary: Natural products and their derivatives have shown to be effective drug candidates against various diseases. This paper reviews potent anticancer, anti-HIV, antibacterial, and antimalarial drugs or lead compounds discovered mainly from 2016 to 2022, as well as computer-assisted techniques used in designing new structures based on available natural products.
Article
Chemistry, Medicinal
Baljinder Singh, Amrita Sharma, Naresh Gunaganti, Mitch Rivers, Pradip K. Gadekar, Brady Greene, Michael Chichioco, Carlos E. Sanz-Rodriguez, Courtney Fu, Catherine LeBlanc, Erin Burchfield, Nyle Sharif, Benjamin Hoffman, Gaurav Kumar, Andrei Purmal, Kojo Mensa-Wilmot, Michael P. Pollastri
Summary: New analogs of the carbazole CBL0137 were synthesized and evaluated, resulting in the discovery of eight compounds with higher or equivalent selectivity indices. Among them, 5v demonstrated potential for drug development against human African trypanosomiasis (HAT), while 5w showed lack of efficacy. Lessons from these studies will guide further optimization of carbazoles for HAT and other indications.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Baljinder Singh, Amrita Sharma, Naresh Gunaganti, Mitch Rivers, Pradip K. Gadekar, Brady Greene, Michael Chichioco, Carlos E. Sanz-Rodriguez, Courtney Fu, Catherine LeBlanc, Erin Burchfield, Nyle Sharif, Benjamin Hoffman, Gaurav Kumar, Andrei Purmal, Kojo Mensa-Wilmot, Michael P. Pollastri
Summary: To develop a candidate drug against human African trypanosomiasis (HAT), researchers synthesized new analogs and evaluated their properties. Eight new compounds with higher or equivalent selectivity indices were identified. Two compounds, 5v and 5w, were tested in a mouse model of HAT, and 5v showed a lead-like profile for drug development while 5w lacked efficacy. These findings will guide further optimization of carbazoles for HAT and other indications.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Pau Nadal Rodriguez, Ouldouz Ghashghaei, Andrea Bagan, Carmen Escolano, Rodolfo Lavilla
Summary: This article introduces a synthetic approach for dealing with the structural complexity of molecules, which offers advantages in terms of synthetic economy and the preparation of larger amounts of drugs. The article summarizes the scientific methodology and main results of the research, provides a general appraisal of the current situation, and offers perspectives on future research directions.
Review
Chemistry, Medicinal
Peng Lei, Jifa Zhang, Peiyu Liao, Changyu Ren, Jiaxing Wang, Yuxi Wang
Summary: CDK12 is a crucial kinase involved in various biological processes and associated with different types of cancer. Development of CDK12 inhibitors has faced challenges due to the similarity with CDK13, however, recent studies have made progress in this field and shed light on the structure-activity relationships for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Junping Pei, Guan Wang, Lu Feng, Jifa Zhang, Tingting Jiang, Qiu Sun, Liang Ouyang
Summary: This article discusses strategies targeting lysosomal pathways and lysosome-based degradation techniques, as well as the advantages and challenges of lysosome-based degrading drugs. These tools can directly regulate protein levels in vivo and provide new strategies for treating diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Monimoy Banerjee, Ishita Hatial, Bradley M. Keegan, Brian S. J. Blagg
Summary: Hsp90 is a molecular chaperone essential for the maturation of diverse client proteins, some of which are cancer targets. Inhibiting Hsp90 activity offers potential for drug development in treating diseases such as cancer. Various assays and technologies are being used to find specific and potent Hsp90-targeting drugs.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Computer Science, Artificial Intelligence
Rajkumar Chakraborty, Yasha Hasija
Summary: The goal of medicinal chemistry is to improve or create new drug molecules for medicine. Generative models use various representations to search for potential hits in unexplored chemical space. In this study, an autoencoder trained on chemical SMILES was used to generate analogues of Vandetanib. Virtual screening and molecular dynamics simulations showed the potential of this approach for lead optimization. The model has a small number of parameters and can generate diverse molecules. The model is available on Google Colaboratory notebook for the scientific community to explore.
EXPERT SYSTEMS WITH APPLICATIONS
(2023)
Review
Pharmacology & Pharmacy
Maureen J. Donlin, Marvin J. Meyers
Summary: Fungal diseases are a major concern in public health, but the development of new antifungals is limited compared to other disease classes. Repurposing existing drugs as antifungals is an approach to quickly provide new treatment options. However, the efficacy and pharmacokinetics of these drug candidates are often suboptimal for fungal diseases. This review discusses the current antifungal drug pipeline and recent strategies to optimize existing drugs into novel molecules with unique modes of action.
DRUG DISCOVERY TODAY
(2022)
Review
Pharmacology & Pharmacy
Amelia Palermo
Summary: Metabolomics enables the analysis of metabolites and lipids in biological systems, and can guide the discovery of lead compounds from natural sources. In combination with other omics, metabolomics can elucidate compound toxicity and mode of action. This article discusses the workflows, limitations, and future opportunities of metabolomics and big data in streamlining pharmaceutical discovery and development.
DRUG DISCOVERY TODAY
(2023)
Article
Biochemistry & Molecular Biology
Andrea Scarpino, Laszlo Petri, Damijan Knez, Timea Imre, Peter abranyi-Balogh, Gyorgy G. Ferenczy, Stanislav Gobec, Gyorgy M. Keseru
Summary: WIDOCK is a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity into AutoDock4. It applies the reactive docking method, extends it into a virtual screening tool, and introduces easy experimental or computational parametrization and a ligand-focused evaluation scheme for validation against therapeutically relevant targets. The protocol has shown high sensitivity in retrieving experimental actives and better performance compared to standard covalent docking tools.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2021)
Article
Biochemistry & Molecular Biology
Andras Gy. Nemeth, Renata Szabo, Gyorgy Orsy, Istvan M. Mandity, Gyorgy M. Keseru, Peter Abranyi-Balogh
Summary: The study developed a convenient continuous-flow procedure for synthesizing thioureas by using an aqueous polysulfide solution, allowing for the application of sulfur under homogeneous and mild conditions. The crystallized products were isolated by simple filtration, with the sulfur retained in the mother liquid.
Article
Chemistry, Organic
Andras Gy Nemeth, Bence Marlok, Attila Domjan, Qinghe Gao, Xinya Han, Gyorgy M. Keseru, Peter Abranyi-Balogh
Summary: A novel one-pot aqueous reaction for the synthesis of 2-iminothiazolines and 2-aminothiazoles using isocyanides, amines, sulfur, and 2'-bromoacetophenones is presented. The procedure features excellent step- and atom-economy, enabling chromatography-free preparation of diversely substituted derivatives.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Review
Chemistry, Physical
Levente M. Mihalovits, Gyorgy G. Ferenczy, Gyorgy M. Keseru
Summary: The recent rise of targeted covalent inhibitors in drug discovery presents new opportunities and challenges for quantum chemical reactivity calculations. These calculations are crucial in determining inhibitory potency by predicting intrinsic reactivities of covalent ligands. Mixed quantum mechanical/molecular mechanical potentials provide a comprehensive description of covalent ligand binding mechanisms, while efficient QM/MM predictions of ligand reactivities are highly useful in covalent drug discovery.
INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Anita Racz, Roberta Palko, Dorottya Csanyi, Zsuzsanna Riedl, David Bajusz, Gyorgy M. Keseru
Summary: This study discovered a series of new MELK inhibitors through virtual screening, and disclosed the synthesis and bioactivity of this class of compounds for the first time, providing a new direction for anti-cancer drug development.
Review
Pharmacology & Pharmacy
Nikolett Peczka, Zoltan Orgovan, Peter Abranyi-Balogh, Gyorgy Miklos Keseru
Summary: This review provides an overview of electrophilic warheads used for protein labeling in chemical biology and medicinal chemistry. The warheads are discussed based on targeted residues, mechanism, and selectivity, and analyzed using multiple datasets. Despite the availability of numerous electrophilic warheads, only a fraction of them are used in current drug discovery projects. Recent studies have identified new tractable residues, but the discovery of new warheads for these residues is still needed.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Review
Pharmacology & Pharmacy
David Bajusz, Gyorgy M. Keseru
Summary: Experimental and virtual screening are complementary approaches that should be integrated in lead discovery settings. Virtual screening can access extremely large synthetically feasible chemical space that can be effectively searched on GPU clusters or cloud architectures. Experimental screening provides reliable datasets by quantitative HTS applications, and DNA-encoded libraries (DEL) have enlarged the chemical space covered by these technologies. These developments, together with the use of artificial intelligence methods, represent new options for their efficient integration. The case studies discussed here demonstrate the benefits of complementary strategies, such as focused and iterative screening.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Chemistry, Medicinal
Amanda E. Wakefield, David Bajusz, Dima Kozakov, Gyoergy M. Keseru, Sandor Vajda
Summary: Despite the limited number of GPCR structures cocrystallized with allosteric inhibitors, protein mapping has revealed the presence of druggable sites at the same locations in a large variety of GPCRs. These sites cluster at nine distinct locations and can be specifically targeted for allosteric modulation across GPCRs. The FTMap server facilitates protein mapping and is freely available for academic and governmental use.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Peter Abranyi-Balogh, Aaron Keeley, Gyorgy G. Ferenczy, Laszlo Petri, Timea Imre, Katarina Grabrijan, Martina Hrast, Damijan Knez, Janez Ilas, Stanislav Gobec, Gyorgy M. Keseru
Summary: The second generation of heterocyclic electrophiles, the quaternized analogue of the heterocyclic covalent fragment library, showed improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH reactivity assay, and thrombin counter screen were used to explain the improved reactivity and selectivity of the N-methylated heterocycles and compare the two generations of heterocyclic electrophiles.
Article
Biochemistry & Molecular Biology
Laszlo Petri, Peter Aabranyi-Balogh, Noemi Csorba, Aaron Keeley, Jozsef Simon, Ivan Randelovic, Jozsef Tovari, Gitta Schlosser, Daniel Szabo, Laszlo Drahos, Gyoergy M. Keseru
Summary: SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Sulfonyl fluorides can label multiple nucleophilic amino acid residues, making them popular in both chemical biology and medicinal chemistry applications. In this study, a small sulfonyl fluoride library was synthesized and characterized, resulting in the identification of a 3-carboxybenzenesulfonyl fluoride warhead for tagging nucleophilic residues. Coupling diverse fragments to this warhead could yield a library of sulfonyl fluoride bits (SuFBits) for screening against protein targets, facilitated by mass spectrometry identification of weak fragments.
Article
Biochemistry & Molecular Biology
David Bajusz, Gaspar Pandy-Szekeres, Agnes Takacs, Elvin D. de Araujo, Gyorgy M. Keseru
Summary: SH2db is a comprehensive structural database and webserver for SH2 domain structures, providing search, browse, and download functions. It assists researchers in their day-to-day work and serves as a valuable resource for SH2 domain-related research.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Physical
Levente M. Mihalovits, Levente Kollar, David Bajusz, Damijan Knez, Kristof Bozovicar, Timea Imre, Gyorgy G. Ferenczy, Stanislav Gobec, Gyorgy M. Keseru
Summary: This study investigates the mechanism of covalent labeling of cysteines using heterocyclic thiones as reversible covalent warheads. The main protease of SARS-CoV-2 harboring Cys145 was chosen as the target, and molecular dynamics simulations and experimental validations were conducted.
Review
Pharmacology & Pharmacy
Noemi Csorba, Peter Abranyi-Balogh, Gyorgy M. Keseru
Summary: Covalent fragment approaches combine the advantages of covalent binders and fragment-based drug discovery (FBDD) for target identification and validation. Recent studies have expanded the chemistries of different warheads to target protein nucleophiles other than cysteine residues. This review discusses these newly developed amino-acid-specific and promiscuous warheads, as well as emerging labeling chemistries. The applications of covalent fragments in the development of molecular glues and proteolysis-targeting chimeras (PROTACs) are highlighted, along with their utility in chemical proteomics-based target identification and validation.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Chemistry, Organic
Andras Gy. Nemeth, Renata Szabo, Krisztina Nemeth, Gyorgy M. Keseru, Peter Abranyi-Balogh
Summary: This study discovered the reactivity of easily accessible electron deficient alkenes towards sulfur and developed a new pseudo-multicomponent reaction for the preparation of polysulfides.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Florent Chevillard, Adam Kelemen, Jillian G. Baker, Vivien A. Aranyodi, Frank Balzer, Peter Kolb, Gyorgy M. Keseru
Summary: A new docking-based fragment evolution approach was developed to extend orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluation of 13,000 extensions for beta(1)- and beta(2)-adrenergic receptors resulted in the synthesis and testing of 112 bitopic molecules, confirming the positive contribution of the secondary binding pocket to potency and selectivity optimizations.
CHEMICAL COMMUNICATIONS
(2021)
