Pub Date : 2024-03-25DOI: 10.1021/acsmedchemlett.4c00093
Hongtao Zhao*,
Structure-based virtual screening has gained momentum again as the high attrition rate at every stage of drug discovery drives the need to explore a greater chemical space. From the Bayesian perspective, its shortcomings as a viable strategy for sustainable hit discovery are discussed, with regard to the prior hit rates of screening libraries and the performance of computational methods. Lessons are shared in selecting virtual hits for experimental validation learned from a series of eight successful campaigns, one of which impacted the discovery of a drug candidate currently in clinical trials.
{"title":"The Science and Art of Structure-Based Virtual Screening","authors":"Hongtao Zhao*, ","doi":"10.1021/acsmedchemlett.4c00093","DOIUrl":"10.1021/acsmedchemlett.4c00093","url":null,"abstract":"<p >Structure-based virtual screening has gained momentum again as the high attrition rate at every stage of drug discovery drives the need to explore a greater chemical space. From the Bayesian perspective, its shortcomings as a viable strategy for sustainable hit discovery are discussed, with regard to the prior hit rates of screening libraries and the performance of computational methods. Lessons are shared in selecting virtual hits for experimental validation learned from a series of eight successful campaigns, one of which impacted the discovery of a drug candidate currently in clinical trials.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140299799","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}
Pub Date : 2024-03-22DOI: 10.1021/acsmedchemlett.4c00037
Darryl Kato*, Regina Wai-Yan Choy, Eda Canales, Ryan A. Dick, April D. Lake, Nathan D. Shapiro, Elbert Chin, Jiayao Li, Jennifer R. Zhang, Qiaoyin Wu, Roland D. Saito, Sammy Metobo, Evangelos Aktoudianakis, Scott D. Schroeder, Zheng-Yu Yang, Dylan M. Glatt, Scott Balsitis, Lindsay Gamelin, Mei Yu, Guofeng Cheng, William E. Delaney IV and John O. Link,
Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.
{"title":"Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873","authors":"Darryl Kato*, Regina Wai-Yan Choy, Eda Canales, Ryan A. Dick, April D. Lake, Nathan D. Shapiro, Elbert Chin, Jiayao Li, Jennifer R. Zhang, Qiaoyin Wu, Roland D. Saito, Sammy Metobo, Evangelos Aktoudianakis, Scott D. Schroeder, Zheng-Yu Yang, Dylan M. Glatt, Scott Balsitis, Lindsay Gamelin, Mei Yu, Guofeng Cheng, William E. Delaney IV and John O. Link, ","doi":"10.1021/acsmedchemlett.4c00037","DOIUrl":"10.1021/acsmedchemlett.4c00037","url":null,"abstract":"<p >Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140205438","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}
Pub Date : 2024-03-21DOI: 10.1021/acsmedchemlett.4c00036
Stephen W. Wright*, Kathleen A. Farley, Seungil Han, John D. Knafels and Katherine L. Lee,
In this paper, we disclose insights on the root causes of three structure–activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all-syn (2S,3S,4S) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.
本文揭示了在发现 IRAK4 抑制剂 Zimlovisertib(PF-06650833)过程中遇到的三种结构-活性关系(SAR)观察结果的根本原因。第一种是异喹啉醚取代基带来的非线性药效 SAR,第二种是氟取代内酰胺带来的药效增强,第三种是氟取代内酰胺对全合成 (2S,3S,4S) 立体化学的轻微药效偏好。我们提供的新数据有助于我们了解这些意想不到的 SAR 趋势的起源。
{"title":"In Retrospect: Root-Cause Analysis of Structure–Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833)","authors":"Stephen W. Wright*, Kathleen A. Farley, Seungil Han, John D. Knafels and Katherine L. Lee, ","doi":"10.1021/acsmedchemlett.4c00036","DOIUrl":"10.1021/acsmedchemlett.4c00036","url":null,"abstract":"<p >In this paper, we disclose insights on the root causes of three structure–activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all-<i>syn</i> (2<i>S</i>,3<i>S</i>,4<i>S</i>) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140200080","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}
Pub Date : 2024-03-21DOI: 10.1021/acsmedchemlett.4c00108
Douglas Armstrong*,
{"title":"59 Years of MIKIW─A Historical Perspective Brought Up-to-Date and an Invitation to Collaborate","authors":"Douglas Armstrong*, ","doi":"10.1021/acsmedchemlett.4c00108","DOIUrl":"10.1021/acsmedchemlett.4c00108","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140200306","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}
Pub Date : 2024-03-19DOI: 10.1021/acsmedchemlett.3c00542
Dahlia R. Weiss, Javier L. Baylon, Ethan D. Evans, Anthony Paiva, Gerry Everlof, Jingfang Cutrone and Fabio Broccatelli*,
The optimization of passive permeability is a key objective for orally available small molecule drug candidates. For drugs targeting the central nervous system (CNS), minimizing P-gp-mediated efflux is an additional important target for optimization. The physicochemical properties most strongly associated with high passive permeability and lower P-gp efflux are size, polarity, and lipophilicity. In this study, a new metric called the Balanced Permeability Index (BPI) was developed that combines these three properties. The BPI was found to be more effective than any single property in classifying molecules based on their permeability and efflux across a diverse range of chemicals and assays. BPI is easy to understand, allowing researchers to make decisions about which properties to prioritize during the drug development process.
{"title":"Balanced Permeability Index: A Multiparameter Index for Improved In Vitro Permeability","authors":"Dahlia R. Weiss, Javier L. Baylon, Ethan D. Evans, Anthony Paiva, Gerry Everlof, Jingfang Cutrone and Fabio Broccatelli*, ","doi":"10.1021/acsmedchemlett.3c00542","DOIUrl":"10.1021/acsmedchemlett.3c00542","url":null,"abstract":"<p >The optimization of passive permeability is a key objective for orally available small molecule drug candidates. For drugs targeting the central nervous system (CNS), minimizing P-gp-mediated efflux is an additional important target for optimization. The physicochemical properties most strongly associated with high passive permeability and lower P-gp efflux are size, polarity, and lipophilicity. In this study, a new metric called the Balanced Permeability Index (BPI) was developed that combines these three properties. The BPI was found to be more effective than any single property in classifying molecules based on their permeability and efflux across a diverse range of chemicals and assays. BPI is easy to understand, allowing researchers to make decisions about which properties to prioritize during the drug development process.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140168288","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}
Pub Date : 2024-03-19DOI: 10.1021/acsmedchemlett.3c00514
Sun Hee Kim*, Sangdon Han, Jian Zhao, Shimiao Wang, Ana Karin Kusnetzow, Greg Reinhart, Melissa A. Fowler, Stacy Markison, Michael Johns, Rosa Luo, R. Scott Struthers, Yunfei Zhu and Stephen F. Betz,
A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure–activity relationship (SAR) studies led to the discovery of 17h (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of 17h suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, 17h was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing’s disease (CD).
{"title":"Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist","authors":"Sun Hee Kim*, Sangdon Han, Jian Zhao, Shimiao Wang, Ana Karin Kusnetzow, Greg Reinhart, Melissa A. Fowler, Stacy Markison, Michael Johns, Rosa Luo, R. Scott Struthers, Yunfei Zhu and Stephen F. Betz, ","doi":"10.1021/acsmedchemlett.3c00514","DOIUrl":"10.1021/acsmedchemlett.3c00514","url":null,"abstract":"<p >A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure–activity relationship (SAR) studies led to the discovery of <b>17h</b> (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of <b>17h</b> suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, <b>17h</b> was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing’s disease (CD).</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140168300","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}
Pub Date : 2024-03-17DOI: 10.1021/acsmedchemlett.3c00496
Dickson Mambwe, Dina Coertzen, Meta Leshabane, Mwila Mulubwa, Mathew Njoroge, Liezl Gibhard, Gareth Girling, Kathryn J. Wicht, Marcus C. S. Lee, Sergio Wittlin, Diogo Rodrigo Magalhães Moreira, Lyn-Marie Birkholtz and Kelly Chibale*,
Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 μM; hERG IC50 = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 μM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 μM, and liver-stage PbHepG2 IC50 = 2.30 μM), good microsomal metabolic stability (MLM CLint < 11 μL·min–1·mg–1, EH < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg–1 resulting from poor permeability (log D7.4 = −0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.
{"title":"hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole","authors":"Dickson Mambwe, Dina Coertzen, Meta Leshabane, Mwila Mulubwa, Mathew Njoroge, Liezl Gibhard, Gareth Girling, Kathryn J. Wicht, Marcus C. S. Lee, Sergio Wittlin, Diogo Rodrigo Magalhães Moreira, Lyn-Marie Birkholtz and Kelly Chibale*, ","doi":"10.1021/acsmedchemlett.3c00496","DOIUrl":"10.1021/acsmedchemlett.3c00496","url":null,"abstract":"<p >Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC<sub>50</sub> = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound <b>1</b> (<i>Pf</i> NF54 IC<sub>50</sub> = 0.012 μM; hERG IC<sub>50</sub> = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound <b>11</b> retained <i>in vitro</i> multistage antiplasmodium activity (ABS <i>Pf</i>NF54 IC<sub>50</sub> = 0.017 μM; gametocytes <i>Pf</i>iGc/<i>Pf</i>LGc IC<sub>50</sub> = 1.24/1.39 μM, and liver-stage <i>Pb</i>HepG2 IC<sub>50</sub> = 2.30 μM), good microsomal metabolic stability (MLM CL<sub>int</sub> < 11 μL·min<sup>–1</sup>·mg<sup>–1</sup>, <i>E</i><sub>H</sub> < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to <b>1</b> and AST, respectively. Despite the excellent <i>in vitro</i> antiplasmodium activity profile, <i>in vivo</i> efficacy in the <i>Plasmodium berghei</i> mouse infection model was diminished, attributable to suboptimal oral bioavailability (<i>F</i> = 14.9%) at 10 mg·kg<sup>–1</sup> resulting from poor permeability (log <i>D</i><sub>7.4</sub> = −0.82). No cross-resistance was observed against 44 common <i>Pf</i> mutant lines, suggesting activity via a novel mechanism of action.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.3c00496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140152339","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}
Pub Date : 2024-03-15DOI: 10.1021/acsmedchemlett.4c00014
Xingye Wu, He Li, Han Liu, Xueyan Ding, Xinting Chen, Chenxi Yin, Yali Gao* and Junjie Ma*,
Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibody-based inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-(o-tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound A5, which showed the most potent inhibition with an IC50 value of 23.78 nM. Meanwhile, based on the results of HTRF assay, the structure–activity relationships (SARs) of the tail were focused on. Cell-based PD-1/PD-L1 blockade assay further revealed that A5 significantly blocked the PD-1/PD-L1 interaction at 1.1 μM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity on Jurkat cells. Moreover, the proposed binding mode of A5 was investigated by a docking analysis. These results indicate that compound A5 is a promising lead compound that deserves further investigation.
{"title":"Design, Synthesis, and Evaluation of 8-(o-Tolyl)quinazoline Derivatives as Small-Molecule PD-1/PD-L1 Antagonists","authors":"Xingye Wu, He Li, Han Liu, Xueyan Ding, Xinting Chen, Chenxi Yin, Yali Gao* and Junjie Ma*, ","doi":"10.1021/acsmedchemlett.4c00014","DOIUrl":"10.1021/acsmedchemlett.4c00014","url":null,"abstract":"<p >Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibody-based inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-(<i>o</i>-tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound <b>A5</b>, which showed the most potent inhibition with an IC<sub>50</sub> value of 23.78 nM. Meanwhile, based on the results of HTRF assay, the structure–activity relationships (SARs) of the tail were focused on. Cell-based PD-1/PD-L1 blockade assay further revealed that <b>A5</b> significantly blocked the PD-1/PD-L1 interaction at 1.1 μM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity on Jurkat cells. Moreover, the proposed binding mode of <b>A5</b> was investigated by a docking analysis. These results indicate that compound <b>A5</b> is a promising lead compound that deserves further investigation.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140152342","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}
DNA-encoded library (DEL) technology is gaining attention for its rapid construction and deconvolution capabilities. Our study explored a novel strategy using rational DELs tailored for the SARS-CoV-2 papain-like protease, which revealed new fragments. Structural changes post-DEL screening mimic traditional medicinal chemistry lead optimization. We unveiled unique aromatic structures offering an alternative optimization path. Notably, we identified superior binding fragments targeting the BL2 groove. Derivative 16 emerged as the most promising by exhibiting IC50 values of 0.25 μM. Derivative 6, which features an aromatic fragment capped with a naphthalene moiety, showed IC50 values of 2.91 μM. Molecular modeling revealed hydrogen bond interactions with Lys157 residue and potential covalent interactions with nearby amino acid residues. This research underscored DEL’s potential for fragment-based drug discovery against SARS-CoV-2 protease.
{"title":"Chemical Space Profiling of SARS-CoV-2 PLpro Using DNA-Encoded Focused Libraries","authors":"Xudong Wang, Ying Zhu, Qingyi Zhao, Weiwei Lu, Yechun Xu, Hangchen Hu* and Xiaojie Lu*, ","doi":"10.1021/acsmedchemlett.4c00069","DOIUrl":"10.1021/acsmedchemlett.4c00069","url":null,"abstract":"<p >DNA-encoded library (DEL) technology is gaining attention for its rapid construction and deconvolution capabilities. Our study explored a novel strategy using rational DELs tailored for the SARS-CoV-2 papain-like protease, which revealed new fragments. Structural changes post-DEL screening mimic traditional medicinal chemistry lead optimization. We unveiled unique aromatic structures offering an alternative optimization path. Notably, we identified superior binding fragments targeting the BL2 groove. Derivative <b>16</b> emerged as the most promising by exhibiting IC<sub>50</sub> values of 0.25 μM. Derivative <b>6</b>, which features an aromatic fragment capped with a naphthalene moiety, showed IC<sub>50</sub> values of 2.91 μM. Molecular modeling revealed hydrogen bond interactions with Lys157 residue and potential covalent interactions with nearby amino acid residues. This research underscored DEL’s potential for fragment-based drug discovery against SARS-CoV-2 protease.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140128666","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}
Pub Date : 2024-03-13DOI: 10.1021/acsmedchemlett.3c00484
Davide Moi*, Serena Vittorio, Andrea Angeli, Claudiu T. Supuran and Valentina Onnis,
A series of 1-(4-sulfamoylbenzoyl)piperidine-4-carboxamides deriving from substituted piperazines/benzylamines was designed, synthesized, and tested on human carbonic anhydrase (hCA). The inhibitory activity of the new sulfonamides was analyzed using acetazolamide (AAZ) as a standard inhibitor against hCA I, II, IX, and XII. Several sulfonamides showed both inhibitory activity at low nanomolar concentrations and selectivity against the cytosolic hCA II isoform, and the same trend was observed on the tumor-associated hCA IX and XII. The benzenesulfonamido carboxamides 11 and 15 were the most potent of the piperazino- and benzylamino-based series, respectively. Docking and molecular dynamics studies related the high selectivity of compound 11 toward the tumor-associated hCA isoforms to its capability to participate in favorable interactions within hCA IX and hCA XII active sites, whereas no such interactions were detected within both hCA I and hCA II isoforms.
研究人员设计、合成了一系列由取代的哌嗪/苄胺衍生的 1-(4-磺酰胺基苯甲酰基)哌啶-4-甲酰胺,并对人碳酸酐酶(hCA)进行了测试。以乙酰唑胺(AAZ)作为标准抑制剂,分析了新型磺酰胺类化合物对 hCA I、II、IX 和 XII 的抑制活性。几种磺酰胺类药物在低纳摩尔浓度下均表现出抑制活性,并对细胞质 hCA II 异构体具有选择性,对肿瘤相关的 hCA IX 和 XII 也表现出同样的趋势。苯磺酰胺基羧酰胺 11 和 15 分别是哌嗪基和苄氨基系列中药效最强的。对接和分子动力学研究表明,化合物 11 对肿瘤相关 hCA 异构体的高选择性与其能够参与 hCA IX 和 hCA XII 活性位点内的有利相互作用有关,而在 hCA I 和 hCA II 异构体内则未检测到此类相互作用。
{"title":"Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors","authors":"Davide Moi*, Serena Vittorio, Andrea Angeli, Claudiu T. Supuran and Valentina Onnis, ","doi":"10.1021/acsmedchemlett.3c00484","DOIUrl":"10.1021/acsmedchemlett.3c00484","url":null,"abstract":"<p >A series of 1-(4-sulfamoylbenzoyl)piperidine-4-carboxamides deriving from substituted piperazines/benzylamines was designed, synthesized, and tested on human carbonic anhydrase (hCA). The inhibitory activity of the new sulfonamides was analyzed using acetazolamide (AAZ) as a standard inhibitor against hCA I, II, IX, and XII. Several sulfonamides showed both inhibitory activity at low nanomolar concentrations and selectivity against the cytosolic hCA II isoform, and the same trend was observed on the tumor-associated hCA IX and XII. The benzenesulfonamido carboxamides <b>11</b> and <b>15</b> were the most potent of the piperazino- and benzylamino-based series, respectively. Docking and molecular dynamics studies related the high selectivity of compound <b>11</b> toward the tumor-associated hCA isoforms to its capability to participate in favorable interactions within hCA IX and hCA XII active sites, whereas no such interactions were detected within both hCA I and hCA II isoforms.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140116262","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}