Article
Pharmacology & Pharmacy
Yang Zhou, Gillian Pereira, Yuanzhang Tang, Matthew James, Miqin Zhang
Summary: Natural polymer-based porous scaffolds with tunable pore size have been developed as three-dimensional tumor models for high-throughput screening of cancer therapeutics. The CHA scaffold-based platform showed potential for mimicking the in vivo malignancy and revealed the influence of pore size on cell growth kinetics, tumor spheroid morphology, gene expression and drug response. The CHA scaffold-based HTS platform demonstrated comparable performance with commercial tissue culture plates and may provide an improved alternative for future cancer study and drug discovery.
Review
Pharmacology & Pharmacy
Yichun Wang, Hyunsu Jeon
Summary: 3D cell cultures play a crucial role in drug discovery and development, but face challenges due to their complexity, time-consuming process, and lack of compatibility with traditional screening protocols. The integration of micro fabrication techniques, automation systems, and high-throughput analytical tools is needed to reveal the effects of therapeutics in 3D cultures.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Athanasios Oikonomou, Luigia Valsecchi, Manuel Quadri, Titus Watrin, Katerina Scharov, Simona Procopio, Jia-Wey Tu, Melina Vogt, Angela Maria Savino, Daniela Silvestri, Maria Grazia Valsecchi, Andrea Biondi, Arndt Borkhardt, Sanil Bhatia, Giovanni Cazzaniga, Grazia Fazio, Michela Bardini, Chiara Palmi
Summary: This study utilized high-throughput drug screening to identify 9 compounds that are active against BCP-ALL but spare normal cells. It also confirmed the anti-leukemic effect of the BCL2 inhibitor venetoclax. This research provides potential therapeutic options for difficult-to-treat childhood BCP-ALL subgroups.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Engineering, Biomedical
Luis P. Ferreira, Vitor M. Gaspar, Luis Mendes, Iola F. Duarte, Joao F. Mano
Summary: The study explores a method for generating organotypic microtumors enriched with dECM, enabling self-assembly with tunable morphological features, with potential applications in drug screening.
Article
Biochemistry & Molecular Biology
Molly L. Churchill, Sarah J. Holdsworth-Carson, Karla J. Cowley, Jennii Luu, Kaylene J. Simpson, Martin Healey, Peter A. W. Rogers, J. F. Donoghue
Summary: Endometriosis is a chronic inflammatory disease that affects a significant portion of women and gender-diverse individuals. This study performed high-throughput compound screens and identified 23 novel compounds with potential therapeutic applications. The study provides valuable insights into the molecular pathophysiology of endometriosis and offers new possibilities for understanding and treating the disease.
Article
Pharmacology & Pharmacy
Noor Mazin Abdulkareem, Raksha Bhat, Reid T. Powell, Soumya Chikermane, Soham Yande, Lisa Trinh, Hala Y. Abdelnasser, Mantasha Tabassum, Alexis Ruiz, Mary Sobieski, Nghi D. Nguyen, Jun Hyoung Park, Camille A. Johnson, Benny A. Kaipparettu, Richard A. Bond, Michael Johnson, Clifford Stephan, Meghana V. Trivedi
Summary: Drug repurposing can overcome the challenges of cost and time in new drug discovery for cancer treatment. In this study, GPCR-targeting drugs were evaluated for their potential in triple-negative breast cancer and drug-resistant HER2+ breast cancer. Nebivolol, a beta-adrenergic receptor-targeting drug, was identified as a promising candidate with inhibitory effects on growth and metastasis in breast cancer cell lines.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Engineering, Biomedical
Haijun Cui, Xueyuan Sun, Marcel Schilling, Christel Herold-Mende, Markus Reischl, Pavel A. A. Levkin, Anna A. A. Popova, Sevin Turcan
Summary: In order to address drug resistance and limited treatment options for recurrent gliomas with IDH1 mutations, a highly miniaturized screening of FDA-approved drugs was conducted using a high-throughput droplet microarray (DMA) platform. Over 20 drugs, including verteporfin (VP), were identified to significantly affect tumorsphere formation and viability. The study also revealed the nuclear pore complex as a potential target for drug development, suggesting a new mechanism of action for VP independent of its known effects on YAP1.
ADVANCED HEALTHCARE MATERIALS
(2023)
Article
Chemistry, Multidisciplinary
Zihan Yang, Zhihang Zhou, Tongxu Si, Zhengdong Zhou, Li Zhou, Y. Rebecca Chin, Liang Zhang, Xinyuan Guan, Mengsu Yang
Summary: Cancer metastasis is a major cause of cancer-related death, and it is characterized by excessive extracellular matrix deposition and increased stiffness in solid tumors. The confined migration of tumor cells in these conditions plays a crucial role in metastasis, but inhibitors specifically targeting this type of migration are rare. In this study, a microfluidic chip was designed to screen for drugs that can effectively inhibit confined migration of cancer cells. By applying this chip, three novel inhibitors of confined migration, MA-5, SB-705498, and diphenyleneiodonium chloride, were discovered in multiple cancer types. The mechanisms of action of these inhibitors were found to be targeting mitochondria, actin polymerization, and cell viability, respectively. Overall, a high-throughput microfluidic platform for screening drugs targeting confined migration was established, and three effective inhibitors were identified.
Article
Oncology
Lei Chen, Yiyi Ji, Ang Li, Bo Liu, Kai Shen, Ruopeng Su, Zehua Ma, Weiwei Zhang, Qi Wang, Yinjie Zhu, Wei Xue
Summary: This study identified fluoxetine, an FDA-approved antidepressant, as a potential therapeutic agent for neuroendocrine prostate cancer (NEPC) through high-throughput drug screening. In vitro and in vivo experiments demonstrated that fluoxetine effectively inhibited neuroendocrine differentiation and cell viability by targeting the AKT pathway. Preclinical tests in NEPC mouse models showed that fluoxetine significantly prolonged overall survival and reduced the risk of tumor distant metastases. These findings repurpose fluoxetine for antitumor application and support its clinical development as a promising therapeutic strategy for NEPC.
FRONTIERS IN ONCOLOGY
(2023)
Review
Multidisciplinary Sciences
Ningna Weng, Zhe Zhang, Yunhan Tan, Xiaoyue Zhang, Xiawei Wei, Qing Zhu
Summary: This article summarizes the background, aim, and key scientific concepts of repurposing antifungal drugs for cancer therapy, and discusses the challenges and perspectives for their future development and clinical applications.
JOURNAL OF ADVANCED RESEARCH
(2023)
Article
Multidisciplinary Sciences
Dorjbal Dorjsuren, Richard T. Eastman, Kathryn J. Wicht, Daniel Jansen, Daniel C. Talley, Benjamin A. Sigmon, Alexey V. Zakharov, Norma Roncal, Andrew T. Girvin, Yevgeniya Antonova-Koch, Paul M. Will, Pranav Shah, Hongmao Sun, Carleen Klumpp-Thomas, Sachel Mok, Tomas Yeo, Stephan Meister, Juan Jose Marugan, Leila S. Ross, Xin Xu, David J. Maloney, Ajit Jadhav, Bryan T. Mott, Richard J. Sciotti, Elizabeth A. Winzeler, Norman C. Waters, Robert F. Campbell, Wenwei Huang, Anton Simeonov, David A. Fidock
Summary: The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials highlights the urgent need to enrich the drug discovery pipeline. A phenotypic quantitative high-throughput screen (qHTS) identified novel dual-active antiplasmodial chemotypes, providing a large-scale resource to investigate and develop novel chemotypes for causal prophylactic antimalarials.
SCIENTIFIC REPORTS
(2021)
Article
Microbiology
Giovanni Di Bonaventura, Veronica Lupetti, Andrea Di Giulio, Maurizio Muzzi, Alessandra Piccirilli, Lisa Cariani, Arianna Pompilio
Summary: Antibiotic resistance calls for new strategies in treating pulmonary infections in CF patients. Repurposing known drugs accelerates drug discovery and development. This study identified five potential hits from a library of 3,386 drugs, with antimicrobial activity against P. aeruginosa, biofilm inhibition, and low toxicity.
MICROBIOLOGY SPECTRUM
(2023)
Article
Cell Biology
Patricia K. Dranchak, Erin Oliphant, Bryan Queme, Laurence Lamy, Yuhong Wang, Ruili Huang, Menghang Xia, Dingyin Tao, James Inglese
Summary: This article introduces a method of high-throughput screening using C. elegans, where phenotypic changes in GFP-expressing organisms guide subsequent analyses. This approach will facilitate the analysis of C. elegans orthologous phenotypes of human pathologies and enable drug library profiling for a range of therapeutic indications.
DISEASE MODELS & MECHANISMS
(2023)
Article
Chemistry, Multidisciplinary
Anqi Yang, Xiang Lin, Zijian Liu, Xin Duan, Yurou Yuan, Jiaxuan Zhang, Qilin Liang, Xianglin Ji, Nannan Sun, Huajun Yu, Weiwei He, Lili Zhu, Bingzhe Xu, Xudong Lin
Summary: A novel in vivo screening strategy combining hierarchically structured biohybrid triboelectric nano-generators (HB-TENGs) arrays with computational bioinformatics analysis for high-throughput pharmacological evaluation using Caenorhabditis elegans is described. The animals' behaviors are efficiently converted into friction deformation through HB-TENGs, and the resulting triboelectric signals are extracted for various bioinformation of the screened compounds. The information-rich electrical readouts are sufficient to predict a drug's identity by multiple-Gaussian-kernels-based machine learning methods.
Article
Chemistry, Multidisciplinary
Jian-hong Gan, Ji-xiang Liu, Yang Liu, Shu-wen Chen, Wen-tao Dai, Zhi-Xiong Xiao, Yang Cao
Summary: Computational identification of new targets for existing drugs is advantageous for drug repurposing, and a parameter-free virtual screening server called DrugRep has been developed to facilitate this process.
ACTA PHARMACOLOGICA SINICA
(2023)
Review
Pharmacology & Pharmacy
Daniel Korn, Andrew J. Thieme, Vinicius M. Alves, Michael Yeakey, Joyce V. V. B. Borba, Stephen J. Capuzzi, Karamarie Fecho, Chris Bizon, Stephen W. Edwards, Rada Chirkova, Christine M. Colvis, Noel T. Southall, Christopher P. Austin, Eugene N. Muratov, Alexander Tropsha
Summary: COPs are a series of key molecular and cellular events underlying therapeutic effects of drug molecules, and their broader use with the help of biomedical knowledge graph mining is likely to accelerate drug discovery and repurposing efforts.
DRUG DISCOVERY TODAY
(2022)
Review
Pharmacology & Pharmacy
Vinicius M. Alves, Daniel Korn, Vera Pervitsky, Andrew Thieme, Stephen J. Capuzzi, Nancy Baker, Rada Chirkova, Sean Ekins, Eugene N. Muratov, Anthony Hickey, Alexander Tropsha
Summary: This article discusses recent advances in biomedical knowledge mining for drug discovery in rare diseases, emphasizing the effectiveness of machine learning and biomedical knowledge graph mining. The power of these methodologies is illustrated through a case study on chordoma.
DRUG DISCOVERY TODAY
(2022)
Article
Environmental Sciences
Joyce V. B. Borba, Vinicius M. Alves, Rodolpho C. Braga, Daniel R. Korn, Kirsten Overdahl, Arthur C. Silva, Steven U. S. Hall, Erik Overdahl, Nicole Kleinstreuer, Judy Strickland, David Allen, Carolina Horta Andrade, Eugene N. Muratov, Alexander Tropsha
Summary: Modern chemical toxicology is in need of reducing, refining, and replacing animal tests. In this study, a collection of computational models called STopTox was developed to predict the toxicity hazard of small organic molecules. The models were validated and shown to have high accuracy. A web portal was also established to assist scientists and regulators in identifying potential toxicants or non-toxicants in chemical libraries of interest.
ENVIRONMENTAL HEALTH PERSPECTIVES
(2022)
Article
Pharmacology & Pharmacy
Cleber C. Melo-Filho, Tesia Bobrowski, Holli-Joi Martin, Zoe Sessions, Konstantin I. Popov, Nathaniel J. Moorman, Ralph S. Baric, Eugene N. Muratov, Alexander Tropsha
Summary: This study identified highly conserved binding sites in key coronavirus proteins, providing important information for the development of broad-spectrum anti-coronaviral medications, and validated the significance of this conservation for drug discovery with existing experimental data.
ANTIVIRAL RESEARCH
(2022)
Article
Chemistry, Medicinal
Renata Priscila Barros de Menezes, Josean Fechine Tavares, Massuo Jorge Kato, Francisco Alex da Rocha Coelho, Airton Lucas Sousa dos Santos, Klinger Antonio da Franca Rodrigues, Zoe L. Sessions, Eugene N. Muratov, Luciana Scotti, Marcus Tullius Scotti
Summary: Chagas disease is a neglected tropical disease endemic in 21 Latin American countries, with a high prevalence in Brazil. This study identified and validated natural products from the Annonaceae family as potential antichagasic agents. The compound 13-Epicupressic acid showed promising activity against the disease.
Article
Chemistry, Medicinal
Marcus Tullius Scotti, Chonny Herrera-Acevedo, Renata Priscila Barros de Menezes, Holli-Joi Martin, Eugene N. Muratov, Avilla Italo de Souza Silva, Emmanuella Faustino Albuquerque, Lucas Ferreira Calado, Ericsson Coy-Barrera, Luciana Scotti
Summary: We introduce MolPredictX, an innovative and freely accessible web interface for predicting the biological activity of query molecules. MolPredictX utilizes in-house QSAR models to provide qualitative predictions and quantitative probabilities for a variety of diseases-related bioactivities.
MOLECULAR INFORMATICS
(2022)
Article
Chemistry, Applied
Andreza Barbosa Silva Cavalcanti, Mayara Dos Santos Maia, Pedro Thiago Ramalho de Figueiredo, Renata Priscila Barros de Menezes, Alex France Messias Monteiro, Roseana Araujo Ramos Meireles, Gabriela Cristina Soares Rodrigues, Ana Rita Rodrigues de Almeida Silva, Jociano da Silva Lins, Laisa Vilar Cordeiro, Valnes S. Rodrigues Junior, Ana Paula O. T. Castelo Branco, Maria de Fatima Agra, Zoe L. Sessions, Eugene N. Muratov, Luciana Scotti, Marcelo Sobral da Silva, Vicente Carlos de Oliveira Costa, Josean Fechine Tavares, Marcus Tullius Scotti
Summary: Plants of the Hyptidinae subtribe, such as Mesosphaerum sidifolium, have been found to contain bioactive molecules with potential as new drug candidates. In this study, the chemical composition of diterpenes isolated from M. sidifolium was analyzed using NMR spectral data. In silico modeling predicted 48 diterpenes with potential biological activity against Mycobacterium tuberculosis. In vitro testing revealed that four compounds showed antimicrobial activity against M. tuberculosis, with Pomiferin D and 1 exhibiting the strongest effect.
NATURAL PRODUCT RESEARCH
(2023)
Article
Toxicology
Vinicius M. Alves, Joyce V. B. Borba, Rodolpho C. Braga, Daniel R. Korn, Nicole Kleinstreuer, Kevin Causey, Alexander Tropsha, Diego Rua, Eugene N. Muratov
Summary: This study developed a computational tool called PreS/MD for rapid and accurate prediction of the guinea pig maximization test (GPMT) outcome. By collecting the largest GPMT results dataset, predictive models were successfully developed using machine learning algorithms, and a publicly accessible web portal was created to predict GPMT outcomes for any molecule of interest. It is expected that this tool will be widely used in medical device safety assessments, helping to replace, reduce, or refine the use of animals in toxicity testing.
TOXICOLOGICAL SCIENCES
(2022)
Article
Microbiology
Natalia Ferreira de Sousa, Helivaldo Diogenes da Silva Souza, Renata Priscila Barros de Menezes, Francinara da Silva Alves, Chonny Alexander Herrera Acevedo, Thais Amanda de Lima Nunes, Zoe L. Sessions, Luciana Scotti, Eugene N. Muratov, Francisco Jaime Bezerra Mendonca-Junior, Klinger Antonio da Franca Rodrigues, Petronio Filgueiras de Athayde Filho, Marcus Tullius Scotti
Summary: The World Health Organization classifies Leishmania as one of the 17 neglected diseases. We analyzed organoselenides for potential anti-leishmanial effects due to their reduced toxicity and displayed biological activity. In silico models predicted the activity of 77 compounds, and subsequent experimental validation confirmed the effectiveness of the methodology, with several compounds showing strong inhibition profiles.
Article
Pharmacology & Pharmacy
Holli-Joi Martin, Cleber C. Melo-Filho, Daniel Korn, Richard T. Eastman, Ganesha Rai, Anton Simeonov, Alexey V. Zakharov, Eugene Muratov, Alexander Tropsha
Summary: We have created a database called SMACC that includes chemogenomics data from ChEMBL for 13 emerging viruses. By solving annotation accuracy challenges, we have collected data for over 32,500 compounds with antiviral properties. This database provides valuable reference for researchers in developing novel drugs to prevent future viral outbreaks.
ANTIVIRAL RESEARCH
(2023)
Article
Chemistry, Medicinal
Amanda Alves de Oliveira, Livia do Carmo Silva, Bruno Junior Neves, Vinicius Alexandre Fiaia Costa, Eugene N. Muratov, Carolina Horta Andrade, Celia Maria de Almeida Soares, Vinicius M. Alves, Maristela Pereira
Summary: This study aims to discover new anti-Paracoccidioides compounds through computational strategies. The researchers collected and curated a library of compounds tested against Paracoccidioides spp., conducted experimental evaluations, and used computational tools to identify potential targets for the most active compounds. Seven compounds showed activity against Paracoccidioides spp., making them potential candidates for developing new compounds.
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Jade Milhomem Lemos, Meryck Felipe Brito da Silva, Alexandra Maria dos Santos Carvalho, Henric Pietro Vicente Gil, Vinicius Alexandre Fiaia Costa, Carolina Horta Andrade, Rodolpho Campos Braga, Philippe Grellier, Eugene N. Muratov, Sebastien Charneau, Jose Teofilo Moreira-Filho, Izabela Marques Dourado Bastos, Bruno Junior Neves
Summary: This study created an explainable multitask pipeline to profile the activity of compounds against three trypanosomes, successfully discovering four new experimental hits, among which LC-6 showed promising results. The results demonstrate that the multitask protocol offers predictivity and interpretability in virtual screening, potentially improving hit rates in Chagas and human African trypanosomiasis projects.
FUTURE MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Joshua E. Hochuli, Sankalp Jain, Cleber Melo-Filho, Zoe L. Sessions, Tesia Bobrowski, Jun Choe, Johnny Zheng, Richard Eastman, Daniel C. Talley, Ganesha Rai, Anton Simeonov, Alexander Tropsha, Eugene N. Muratov, Bolormaa Baljinnyam, Alexey Zakharov
Summary: This study investigates whether compounds that bind the human angiotensin-converting enzyme 2 (ACE2) protein can reduce SARS-CoV-2 replication without affecting ACE2's enzymatic function. Through screening and in silico techniques, 73 ACE2 binders were identified, and five of them were found to inhibit the viral life cycle in human cells. These compounds serve as valuable starting points for the development of acute treatments for COVID-19 and research into host-directed therapy.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)
Article
Chemistry, Medicinal
Renata Priscila Barros de Menezes, Josean Fechine Tavares, Massuo Jorge Kato, Francisco Alex da Rocha Coelho, Holli-Joi Martin, Eugene Muratov, Airton Lucas Sousa dos Santos, Klinger Antonio da Franca Rodrigues, Luciana Scotti, Marcus Tullius Scotti
Summary: Leishmaniasis is a neglected tropical disease with outdated and variable drug treatments. This study utilized predictive models to screen potentially active compounds from specialized metabolites of Annonaceae against Leishmania amazonensis. Several substances showed leishmanicidal activity, with lupeol exhibiting the best activity. These findings hold promise for the development of new therapeutical agents for leishmaniasis based on natural products.
REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY
(2022)
Article
Biochemistry & Molecular Biology
Renata Priscila Barros de Menezes, Jessika de Oliveira Viana, Eugene Muratov, Luciana Scotti, Marcus Tullius Scotti
Summary: This study combined ligand-based and structure-based virtual screening techniques to select five potentially active alkaloids against S. mansoni. Two of these alkaloids showed plausible toxicity, metabolomics, and toxicity profiles, making them promising candidates for the development of new schistosomicidal compounds based on natural products.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2022)