Retrospective Analysis of Chemical Structure-Based in silico Prediction of Primary Drug Target and Off-Targets

Takai, Takafumi; Jeffy, Brandon D.; Prabhu, S.; Cohen, Jennifer D.

doi:10.1016/j.comtox.2023.100273

Cited by 3 publications

References 43 publications

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In vitro human ion channel assays predictive of drug-induced seizure

Cohen,

You,

Sharma

et al. 2024

Toxicological Sciences

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Seizure is among the most severe FDA black box warnings of neurotoxicity reported on drug labels. Gaining a better mechanistic understanding of off-targets causative of seizure will improve identification of potential seizure risks preclinically. In the present study, we evaluated an in vitro panel of 9 investigational (Cav2.1, Cav3.2, GlyRA1, AMPA, HCN1, Kv1.1, Kv7.2/7.3, NaV1.1, Nav1.2) and 2 standard (GABA-A, NMDA) ion channel targets with strong correlative links to seizure, using automated electrophysiology. Each target was assessed with a library of 34 preclinical compounds and 10 approved drugs with known effects of convulsion in vivo and/or in patients. Cav2.1 had the highest frequency of positive hits, 20 compounds with an EC30 or IC30 ≤ 30 µM, and highest importance score relative to the 11 targets. An additional 35 approved drugs, with categorized low to frequent seizure risk in patients, were evaluated in the Cav2.1 assay. The Cav2.1 assay predicted preclinical compounds to cause convulsion in nonclinical species with a sensitivity of 52% and specificity of 78%, and approved drugs to cause seizure in nonclinical species or in patients with a sensitivity of 48% or 54% and specificity of 71% or 78%, respectively. The integrated panel of 11 ion channel targets predicted preclinical compounds to cause convulsion in nonclinical species with a sensitivity of 68%, specificity of 56%, and accuracy of 65%. This study highlights the utility in expanding the in vitro panel of targets evaluated for seizurogenic activity, in order to reduce compound attrition early on in drug discovery.

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In vitro human ion channel assays predictive of drug-induced seizure

Cohen,

You,

Sharma

et al. 2024

Toxicological Sciences

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WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Modekurty

2024

Preprint

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Background: Oxaliplatin is the standard treatment option for colorectal cancer (CRC) which is one of the most prevalent forms of cancer. However, patients suffer either treatment discontinuation or adverse post-treatment life quality due to Oxaliplatin-induced peripheral neuropathy. Methods: Our study has comprehensively explored the molecular mechanisms underlying Oxaliplatin-induced peripheral neuropathy via an extensive literature survey and identified multiple genes that may contribute to neuropathy and neurotoxicity. In addition to that, the publicly available bulk transcriptomic data of Illumina HiSeq 2500 platform, comprising the CRC tissue of 18 individuals' tumor and adjacent normal tissue was processed to identify differentially expressed genes (DEGs). Moreover, the single-cell RNA sequencing data of 10X genomics comprising normal and tumor tissues was subjected to analysis using Seurat and sctype R packages to uncover the cancer cells associated DEGs. Functional and pathway enrichment analysis was conducted using the Genecodis4 web-based tool. Next, RNA-seq data of CRC cell lines treated with Oxaliplatin compared with normal individuals, was also processed and DEGs were determined to validate the inhibition of a curated list of neuropathy-associated genes. Results: From literature and database searches, a total of 1367 genes, including ion channel genes, normal sensory neuron-associated genes, and axon-excitability-related genes were collected that are either reported to be or may be contributing to neuropathy among cancer survivors upon oxaliplatin administration. The bulk transcriptomic data analysis revealed 715 DEGs and single-cell analysis uncovered 2,854 DEGs. Identified upregulated genes from single-cell data analysis, such as LGALS4, SPINK4, TFF3, REG4, and REG1A were found to be associated with tumor proliferation via epithelial-mesenchymal transitions, oxidative stress, dysregulated immune system, and inflammation which can be utilized as potential targets to devise novel therapeutic strategies for CRC treatment. Furthermore, many proteins involved in axon-excitability (NGF, SOD1, ROBO1, CNTNAP2, CNTNAP2, and KCNMB1), normal sensory neuron (SOX10, APOE, SST, S1PR1, and KCND3), voltage-gated sodium (SCNN1B, SCNN1G, SCNN1A, SCN1B, and SCN2B), calcium (CACNA2D2, CACNA1A, CACNA1C, CACNA1E, and CACNA1F), and potassium channels (KCND3, KCNMB1, KCNMA1, KCNJ2, and KCNN4) showed downregulation due to the oxaliplatin administration in CRC cell lines and their inhibition may have led to neuropathy which needs further validations. Conclusion: Our study uncovers the downregulation of multiple genes upon oxaliplatin administration leading to neuropathy development and also elucidates potential therapeutic targets for better prognosis of CRC.

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Investigating the anti-carcinogenic potential action of 1,2,3 triazole core compounds: impact of introducing an aldehyde or Nitro group, integrating cell line studies, and in silico ADME and protein target prediction

Ghassan Hameed,

Sahib,

Sabbar Omran

2024

PHAR

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The development of novel chemotherapeutic drugs begins with the suppression of cancer and angiogenesis. Ringed compounds with one or more heteroatoms are known as heterocyclic compounds. In organic chemistry and the pharmaceutical sector, heterocyclic compounds containing nitrogen atoms are valuable. In pharmaceutical chemistry, molecules containing a 1,2,3-triazole skeleton are particularly favored. They have great stability, making it simple to bind them to biomolecular targets. In this work, two 1,2,3-triazole scaffolds containing new chemical entities were assessed using the MTT assay against two malignant (MCF-7 and HCT116) and one normal (HUVECs) cell lines with the goal of creating a new leading prodrug for cancer treatment. The ligands were well characterized by FTIR and 1HNMR. In silico ADMET studies show acceptable pharmacokinetic properties. With the aid of the ligands’ SWISS target protein prediction, the in silico binding to target proteins was examined. The two compounds exhibited a dose-dependent cytotoxic effect, with the H4 compound demonstrating a favorable selectivity index against MCF-7 breast cancer, indicating its potential as a leading compound for anticancer prodrugs.

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Retrospective Analysis of Chemical Structure-Based in silico Prediction of Primary Drug Target and Off-Targets

Cited by 3 publications

References 43 publications

In vitro human ion channel assays predictive of drug-induced seizure

In vitro human ion channel assays predictive of drug-induced seizure

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

Investigating the anti-carcinogenic potential action of 1,2,3 triazole core compounds: impact of introducing an aldehyde or Nitro group, integrating cell line studies, and in silico ADME and protein target prediction

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