Article
Oncology
Vladimir Shapovalov, Liliya Kopanitsa, Lavinia-Lorena Pruteanu, Graham Ladds, David S. Bailey
Summary: Glioblastoma remains a challenging cancer with limited treatment options, and future therapies will require personalized approaches targeting aggressive cellular phenotypes. The use of DIGEX has identified genes encoding drug targets and validated effective antiproliferative agents in human GBM cell models. Further research using this method may uncover new therapeutic opportunities and diagnostic strategies for the complex drug response networks in GBM.
Article
Biochemistry & Molecular Biology
Kaiyang Liu, Xi Chen, Yue Ren, Chaoqun Liu, Tianyi Lv, Ya'nan Liu, Yanling Zhang
Summary: Polypharmacology has emerged as a new paradigm in drug discovery, playing a crucial role in addressing polygenic diseases. This paper introduces multi-target-based polypharmacology prediction (mTPP), an approach that employs virtual screening and machine learning to explore the relationship between the action of multiple targets and the overall efficacy of drugs. Through the mTPP model, potential hepatoprotective components and candidates with potential effects against drug-induced liver injury (DILI) are identified. The model demonstrates accuracy in predicting the viabilities of APAP-induced injury cells, indicating its potential for aiding the development of polypharmacology and the discovery of multi-target drugs.
CHEMICO-BIOLOGICAL INTERACTIONS
(2022)
Review
Pharmacology & Pharmacy
Melissa S. Love, Case W. McNamara
Summary: Recent advancements in drug discovery efforts for cryptosporidiosis have been inspired by the challenges posed by the unique biology of Cryptosporidium. Phenotypic-based screens and repositioning of hits from other pathogens have created a pipeline of potential therapeutics for this disease. Improved methodologies in phenotypic assays are facilitating the development of new compounds for clinical testing.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Article
Pharmacology & Pharmacy
Christopher A. A. Lipinski, Andrew G. G. Reaume
Summary: A target-based drug discovery strategy has led to a bias away from low molecular weight (MWT) drug discovery. However, historical evidence and the example of MLR-1023 show that drugs can be found among low MWT compounds. Low MWT compounds are more suited to identification of new therapeutic activity using phenotypic screens, and their commercial availability facilitates biology study. Concerns about on-target and off-target therapeutic activities arise from a concern that either phenotypic or low MWT drug discovery might bias towards promiscuous compounds.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mubashir Aziz, Syeda Abida Ejaz, Seema Zargar, Naveed Akhtar, Abdullahi Tunde Aborode, Tanveer A. Wani, Gaber El-Saber Batiha, Farhan Siddique, Mohammed Alqarni, Ashraf Akintayo Akintola
Summary: NEK7 has a crucial role in cell division and inflammation, making it a potential drug target for cancer treatments. Virtual screening identified a compound with superior binding energy, showing promise as a potential inhibitor for NEK7.
Article
Pharmacology & Pharmacy
Peng Li, Chujie Bai, Lingmin Zhan, Haoran Zhang, Yuanyuan Zhang, Wuxia Zhang, Yingdong Wang, Jinzhong Zhao
Summary: Identifying the biological targets of a compound is crucial for understanding drug mechanisms and developing new drugs. The Connectivity Map concept connects genes, drugs, and diseases based on gene-expression signatures. However, existing methods are inefficient due to the need for reference drugs. In this study, we developed a procedure to extract target-induced gene modules and identified target gene clusters. Additionally, we proposed a gene module pair-based approach to predict novel compound-target interactions, leading to the discovery of new inhibitors for PI3K pathway proteins.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Nil Ege, Habib Bouguenina, Marianthi Tatari, Rajesh Chopra
Summary: This review provides a detailed summary of recent advances in understanding the mechanism of action of emerging protein degradation therapies, focusing on the use of phenotypic screening and chemical properties for drug discovery. By defining rules for selecting neo-substrates for degradation and exploring alternative E3 ligases, researchers are making significant progress in this field.
CELL CHEMICAL BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Sean Vandersluis, Jennifer C. Reid, Luca Orlando, Mickie Bhatia
Summary: The research highlights the limited success in the clinic of effective drugs for cancer patients, and the need for careful evaluation of high attrition rates in current drug development approaches. A meta-analysis of 2918 clinical studies involving 466 drugs for acute myeloid leukemia (AML) was conducted to determine key shared pre-clinical characteristics that relate to successful or unsuccessful drugs in patients. The recommendation is to use phenotypic drug discovery during pre-clinical development, informing and improving foundational discovery screens and platforms for other cancers.
DRUG DISCOVERY TODAY
(2022)
Article
Chemistry, Physical
Qiushuang Gao, Peng Yao, Ying Wang, Qizheng Yao, Ji Zhang
Summary: In this study, in silico simulations and drug repurposing approaches were used to identify promising HDAC2 inhibitors. Compounds DB08464, DB00731, DB13930, and DB13696 showed stable binding to HDAC2 and favorable interactions. Additionally, one of the screened compounds, the antiviral drug DB13696, exhibited significant anti-proliferative activity on HepG2 cells with high HDAC2 expression.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Genetics & Heredity
Zhiting Wei, Sheng Zhu, Xiaohan Chen, Chenyu Zhu, Bin Duan, Qi Liu
Summary: Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as connectivity map (CMap) and library of integrated network-based cellular signatures (LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed. Among them, the fundamental issue is to define the proper similarity between transcriptional profiles. To address this issue, the learning-based framework DrSim is developed, which automatically infers similarity instead of defining it. Evaluation on publicly available datasets shows that DrSim outperforms existing methods in drug annotation and repositioning.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2022)
Article
Pharmacology & Pharmacy
Huizhen Ge, Lizeng Peng, Zhou Sun, Huanxiang Liu, Yulin Shen, Xiaojun Yao
Summary: In this study, novel HPK1 inhibitors were identified using virtual screening and kinase inhibition assays. Molecular dynamics simulations were performed to analyze the interaction between the identified compounds and HPK1 kinase domain. The most potent compound showed potential for further development as an HPK1 inhibitor for immunotherapy.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Tianduanyi Wang, Otto I. Pulkkinen, Tero Aittokallio
Summary: Most drug molecules have the ability to modulate multiple target proteins, which can lead to both therapeutic effects and unwanted side effects. Evaluating the selectivity of a compound is an important factor in drug development and repurposing efforts. Traditional methods for characterizing selectivity fall short in quantifying how selective a compound is against a particular target protein. In this study, we propose an optimization-based selectivity scoring method that allows for the identification of potent and selective compounds against given kinase targets. We demonstrate the effectiveness of this method in finding highly selective compounds in computational experiments using a large-scale kinase inhibitor dataset.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tatiana Saporiti, Mauricio Cabrera, Josefina Bentancur, Maria Elisa Ferrari, Nallely Cabrera, Ruy Perez-Montfort, Francisco J. Aguirre-Crespo, Jorge Gil, Ulises Cuore, Dimitris Matiadis, Marina Sagnou, Guzman Alvarez
Summary: Rhipicephalus microplus, the common cattle tick, is a major ectoparasite in livestock causing significant economic and health losses. There is an urgent need to find alternatives for controlling resistant ticks since all currently available acaricides have reported resistance. This study discovered compounds derived from natural sources and synthetic organic molecules that showed potential as acaricidal agents against resistant ticks, with minimal toxicity to mammalian cells.
Review
Chemistry, Medicinal
Xing-Jie Dai, Lei-Peng Xue, Shi-Kun Ji, Ying Zhou, Ya Gao, Yi-Chao Zheng, Hui-Min Liu, Hong-Min Liu
Summary: In recent years, triazole-fused pyrimidines, a widely-used class of heterocycles in medicinal chemistry, have shown potential as anticancer agents that target various cancer-associated targets. This review focuses on the latest advancements in triazole-pyrimidines as target-based anticancer agents, published between 2007 and 2022. The review also discusses the structure-activity relationships (SARs) and multiple pathways to facilitate the development of more effective and biotargeted anticancer candidates.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Richi Sakaguchi, Saki Nakamura, Hiroyuki Iha, Masaki Tanaka
Summary: Currently, in vitro phenotypic screening methods are widely used for drug discovery. In the field of epilepsy research, measurements of neuronal activities have been utilized for predicting efficacy of anti-epileptic drugs. Researchers have developed a high-throughput screening system with a new analysis method for quantifying waveforms, allowing simultaneous measurement of calcium oscillations in a 96-well plate. The characterization of anti-epileptic drugs and prediction of novel drug candidates' mechanism of action can be achieved by focusing on the features of calcium oscillations using principal component analysis.
