ACS Medicinal Chemistry Letters最新文献

In This Issue, Volume 15, Issue 12

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-12 DOI: 10.1021/acsmedchemlett.4c0056310.1021/acsmedchemlett.4c00563

Michelle A. Estrada,

引用次数: 0

Supervised Screening of EGFR Inhibitors Validated through Computational Structural Biology Approaches

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 DOI: 10.1021/acsmedchemlett.4c0038510.1021/acsmedchemlett.4c00385

Aamir Mehmood, Daixi Li, Jiayi Li, Aman Chandra Kaushik* and Dong-Qing Wei*,

{"title":"Supervised Screening of EGFR Inhibitors Validated through Computational Structural Biology Approaches","authors":"Aamir Mehmood, Daixi Li, Jiayi Li, Aman Chandra Kaushik* and Dong-Qing Wei*, ","doi":"10.1021/acsmedchemlett.4c0038510.1021/acsmedchemlett.4c00385","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00385https://doi.org/10.1021/acsmedchemlett.4c00385","url":null,"abstract":"One of the prominent challenges in breast cancer (BC) treatment is human epidermal growth factor receptor (EGFR) overexpression, which facilitates tumor proliferation and presents a viable target for anticancer therapies. This study integrates multiomics data to pinpoint promising therapeutic compounds and employs a machine learning (ML)-based similarity search to identify effective alternatives. We used BC cell line data from the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases and single-cell RNA sequencing (scRNA-seq) information that established afatinib as an efficacious candidate demonstrating superior IC50 values. Next, ML models, including support vector machine (SVM), artificial neural networks (ANN), and random forest (RF), were trained on ChEMBL data to classify compounds with similar activity to the reference drug as active or inactive. The promising candidates underwent computational structural biology assessments for their molecular interactions and conformational dynamics. Our findings indicate that compounds ChEMBL233324, ChEMBL233325, ChEMBL234580, and ChEMBL372692 exhibit potent repressive action against EGFR, underscoring their potential as active antibreast cancer agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2190–2200 2190–2200"},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00420

Bruna K P Sousa, Melina Mottin, Donald Seanego, Christopher D Jurisch, Beatriz S A Rodrigues, Verônica L S da Silva, Milene Aparecida Andrade, Gilberto S Morais, Diogo F Boerin, Thamires Q Froes, Flávia Nader Motta, M Cristina Nonato, Izabela D M Bastos, Kelly Chibale, Richard K Gessner, Carolina Horta Andrade

{"title":"Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation.","authors":"Bruna K P Sousa, Melina Mottin, Donald Seanego, Christopher D Jurisch, Beatriz S A Rodrigues, Verônica L S da Silva, Milene Aparecida Andrade, Gilberto S Morais, Diogo F Boerin, Thamires Q Froes, Flávia Nader Motta, M Cristina Nonato, Izabela D M Bastos, Kelly Chibale, Richard K Gessner, Carolina Horta Andrade","doi":"10.1021/acsmedchemlett.4c00420","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00420","url":null,"abstract":"The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC50 of 73.61 μM and a K i of 22 μM. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC50 values between 15.06 and 51.81 μM. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2140-2149"},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Supervised Screening of EGFR Inhibitors Validated through Computational Structural Biology Approaches.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00385

Aamir Mehmood, Daixi Li, Jiayi Li, Aman Chandra Kaushik, Dong-Qing Wei

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引用次数: 0

Synthesis and Evaluation of Halogenated Pralidoximes in Reactivation of Organophosphate-Inhibited Cholinesterases

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 DOI: 10.1021/acsmedchemlett.4c0046410.1021/acsmedchemlett.4c00464

Karolina Knittelova, Eliska Prchalova, Adela Fuchsova, Rudolf Andrys, Zuzana Kohoutova, Sara Rademacherova, Lukas Prchal, Kamil Musilek and David Malinak*,

{"title":"Synthesis and Evaluation of Halogenated Pralidoximes in Reactivation of Organophosphate-Inhibited Cholinesterases","authors":"Karolina Knittelova, Eliska Prchalova, Adela Fuchsova, Rudolf Andrys, Zuzana Kohoutova, Sara Rademacherova, Lukas Prchal, Kamil Musilek and David Malinak*, ","doi":"10.1021/acsmedchemlett.4c0046410.1021/acsmedchemlett.4c00464","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00464https://doi.org/10.1021/acsmedchemlett.4c00464","url":null,"abstract":"Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed. The oximes were designed with a halogen substituent that lowers the pKa and enhances oximate formation. Their synthesis, stability, physicochemical properties, inhibition of native cholinesterases, and in vitro reactivation of organophosphate-inhibited cholinesterases were investigated. A series of C4 and C6 halogenated oximes showed instability and their degradation products were identified, while C3 and C5 oximes exhibited sufficient stability for the evaluation. C3 oximes displayed overall low inhibition of cholinesterases and high reactivation ability of organophosphate-inhibited cholinesterases compared to pralidoxime, indicating the significant impact of halogen substitution on reactivation ability.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2181–2189 2181–2189"},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 DOI: 10.1021/acsmedchemlett.4c0042010.1021/acsmedchemlett.4c00420

Bruna K. P. Sousa, Melina Mottin, Donald Seanego, Christopher D. Jurisch, Beatriz S. A. Rodrigues, Verônica L. S. da Silva, Milene Aparecida Andrade, Gilberto S. Morais Junior, Diogo F. Boerin, Thamires Q. Froes, Flávia Nader Motta, M. Cristina Nonato, Izabela D. M. Bastos, Kelly Chibale, Richard K. Gessner and Carolina Horta Andrade*,

{"title":"Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation","authors":"Bruna K. P. Sousa, Melina Mottin, Donald Seanego, Christopher D. Jurisch, Beatriz S. A. Rodrigues, Verônica L. S. da Silva, Milene Aparecida Andrade, Gilberto S. Morais Junior, Diogo F. Boerin, Thamires Q. Froes, Flávia Nader Motta, M. Cristina Nonato, Izabela D. M. Bastos, Kelly Chibale, Richard K. Gessner and Carolina Horta Andrade*, ","doi":"10.1021/acsmedchemlett.4c0042010.1021/acsmedchemlett.4c00420","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00420https://doi.org/10.1021/acsmedchemlett.4c00420","url":null,"abstract":"The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC50 of 73.61 μM and a Ki of 22 μM. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC50 values between 15.06 and 51.81 μM. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2140–2149 2140–2149"},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00420","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and Evaluation of Halogenated Pralidoximes in Reactivation of Organophosphate-Inhibited Cholinesterases.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00464

Karolina Knittelova, Eliska Prchalova, Adela Fuchsova, Rudolf Andrys, Zuzana Kohoutova, Sara Rademacherova, Lukas Prchal, Kamil Musilek, David Malinak

{"title":"Synthesis and Evaluation of Halogenated Pralidoximes in Reactivation of Organophosphate-Inhibited Cholinesterases.","authors":"Karolina Knittelova, Eliska Prchalova, Adela Fuchsova, Rudolf Andrys, Zuzana Kohoutova, Sara Rademacherova, Lukas Prchal, Kamil Musilek, David Malinak","doi":"10.1021/acsmedchemlett.4c00464","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00464","url":null,"abstract":"Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed. The oximes were designed with a halogen substituent that lowers the pK a and enhances oximate formation. Their synthesis, stability, physicochemical properties, inhibition of native cholinesterases, and in vitro reactivation of organophosphate-inhibited cholinesterases were investigated. A series of C4 and C6 halogenated oximes showed instability and their degradation products were identified, while C3 and C5 oximes exhibited sufficient stability for the evaluation. C3 oximes displayed overall low inhibition of cholinesterases and high reactivation ability of organophosphate-inhibited cholinesterases compared to pralidoxime, indicating the significant impact of halogen substitution on reactivation ability.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2181-2189"},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to “Evaluation of High-Affinity Monoclonal Antibodies and Antibody-Drug Conjugates by Homogenous Time-Resolved FRET”

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-29 DOI: 10.1021/acsmedchemlett.4c0055510.1021/acsmedchemlett.4c00555

Harmon Greenway, and , Jin Wang*,

引用次数: 0

Highly Sensitive Naphthalene-Based Twisted Intramolecular Charge Transfer Molecules for the Detection of In Vitro and In Cellulo Protein Aggregates

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-29 DOI: 10.1021/acsmedchemlett.4c0036310.1021/acsmedchemlett.4c00363

Joy Debnath*, Yuvasree Sekar and Anwesha Bera,

引用次数: 0

Correction to "Evaluation of High-Affinity Monoclonal Antibodies and Antibody-Drug Conjugates by Homogenous Time-Resolved FRET".