ACS Bio & Med Chem Au最新文献

{"title":"Problematic Attributions of Entropic and Hydrophobic Effects in Drug Interactions","authors":"Hans-Jörg Schneider*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0014810.1021/acsbiomedchemau.4c00148","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00148https://doi.org/10.1021/acsbiomedchemau.4c00148","url":null,"abstract":"<p >The ΔG affinity of drugs with biopolymers and the underling noncovalent interactions play an essential role in drug discovery. Supramolecular complexes can be designed for the identification and quantification of specific interactions, including their dependence on the medium; they also secure the additivity of ΔΔG increments. Such analyses have helped to clarify hydrophobic effects in intermolecular associations, which are barely measurable with small alkyl groups, but large in the presence of curved surfaces in which the replacement of hydrogen bond-deficient water molecules by a ligand leads to sizable enthalpy gain. Difficult to predict entropy contributions TΔS to ΔG vary between 5% and over 90%, particularly in drug associations, as is obvious from literature data. As illustrated with several drug complexes, many so-called hydrophobic effects involve in fact van der Waals or dispersive interactions. Measurements with supramolecular porphyrin complexes allowed us to derive dispersive binding contributions for many groups, which exhibit a correlation with polarizability. In consequence, heteroatoms or π-systems always lead to enhanced van der Waals contributions, while for hydrophobic effects the opposite is expected. Binding contributions from supramolecular complexes can in the future also help artificial intelligence approaches in drug discovery, by expansion of hybrid databases with potential ligands containing groups with desired binding contributions.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"334–341 334–341"},"PeriodicalIF":3.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Problematic Attributions of Entropic and Hydrophobic Effects in Drug Interactions.","authors":"Hans-Jörg Schneider","doi":"10.1021/acsbiomedchemau.4c00148","DOIUrl":"10.1021/acsbiomedchemau.4c00148","url":null,"abstract":"<p><p>The ΔG affinity of drugs with biopolymers and the underling noncovalent interactions play an essential role in drug discovery. Supramolecular complexes can be designed for the identification and quantification of specific interactions, including their dependence on the medium; they also secure the additivity of ΔΔG increments. Such analyses have helped to clarify hydrophobic effects in intermolecular associations, which are barely measurable with small alkyl groups, but large in the presence of curved surfaces in which the replacement of hydrogen bond-deficient water molecules by a ligand leads to sizable enthalpy gain. Difficult to predict entropy contributions TΔS to ΔG vary between 5% and over 90%, particularly in drug associations, as is obvious from literature data. As illustrated with several drug complexes, many so-called hydrophobic effects involve in fact van der Waals or dispersive interactions. Measurements with supramolecular porphyrin complexes allowed us to derive dispersive binding contributions for many groups, which exhibit a correlation with polarizability. In consequence, heteroatoms or π-systems always lead to enhanced van der Waals contributions, while for hydrophobic effects the opposite is expected. Binding contributions from supramolecular complexes can in the future also help artificial intelligence approaches in drug discovery, by expansion of hybrid databases with potential ligands containing groups with desired binding contributions.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"334-341"},"PeriodicalIF":3.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ACS Bio & Med Chem Au</i>: Introducing the 2024 Rising Stars in Biological, Medicinal, and Pharmaceutical Chemistry.","authors":"Squire J Booker","doi":"10.1021/acsbiomedchemau.5c00080","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00080","url":null,"abstract":"","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"227-234"},"PeriodicalIF":3.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACS Bio & Med Chem Au: Introducing the 2024 Rising Stars in Biological, Medicinal, and Pharmaceutical Chemistry","authors":"Squire J. Booker,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0008010.1021/acsbiomedchemau.5c00080","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00080https://doi.org/10.1021/acsbiomedchemau.5c00080","url":null,"abstract":"","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"227–234 227–234"},"PeriodicalIF":3.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA G‑Quadruplex Reprogramming with Guanine-Rich Antisense Oligonucleotides Inhibits Monoamine Oxidase B's Translation.","authors":"Marc-Antoine Turcotte, Jean-Pierre Perreault","doi":"10.1021/acsbiomedchemau.5c00004","DOIUrl":"10.1021/acsbiomedchemau.5c00004","url":null,"abstract":"<p><p>The human transcriptome contains secondary RNA structures like RNA G-quadruplexes (rG4s) which regulate biological processes such as translation by ribosome stalling. Canonical rG4s, which are stabilized by both Hoogsteen hydrogen bonds and potassium ions, are known to hinder translation in the 5' untranslated region (5'UTR) of mRNAs. In neurodegenerative diseases, including Parkinson's disease (PD), rG4s have been shown to influence protein synthesis. However, the impact of rG4s in nonmutated therapeutic targets like monoamine oxidase B (MAOB), an enzyme involved in dopamine metabolism, remains unexplored. In this study, an rG4 located in the MAOB mRNA's 5'UTR was identified, and ways to either stabilize or reprogram this rG4 were explored. The translation inhibitory role of the rG4 was demonstrated both <i>in vitro</i> and <i>in cellulo</i> and was shown to be further accentuated in the presence of the PhenDC3 ligand. As an alternative to ligands, which cannot specifically stabilize only one G4, the MOAB rG4 was reprogrammed with G-rich antisense oligonucleotides (G-ASOs) from a two-quartets to three-quartets G4. The G-ASOs, either unmodified DNA or 2'OMe, were shown to both induce a new rG4 folding through intermolecular interactions and to specifically reduce the translation of MAOB both <i>in vitro</i> and <i>in cellulo</i>. These findings propose a targeted approach with which to modulate rG4 structures for therapeutics, suggesting that rG4 folding, when stabilized by G-ASOs, could regulate protein synthesis and even potentially alleviate PD symptoms by reducing MAOB activity. This approach opens new avenues as it could be used to reduce the expression of many therapeutic protein targets.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"403-414"},"PeriodicalIF":3.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA G-Quadruplex Reprogramming with Guanine-Rich Antisense Oligonucleotides Inhibits Monoamine Oxidase B’s Translation","authors":"Marc-Antoine Turcotte,&nbsp; and ,&nbsp;Jean-Pierre Perreault*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0000410.1021/acsbiomedchemau.5c00004","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00004https://doi.org/10.1021/acsbiomedchemau.5c00004","url":null,"abstract":"<p >The human transcriptome contains secondary RNA structures like RNA G-quadruplexes (rG4s) which regulate biological processes such as translation by ribosome stalling. Canonical rG4s, which are stabilized by both Hoogsteen hydrogen bonds and potassium ions, are known to hinder translation in the 5′ untranslated region (5′UTR) of mRNAs. In neurodegenerative diseases, including Parkinson’s disease (PD), rG4s have been shown to influence protein synthesis. However, the impact of rG4s in nonmutated therapeutic targets like monoamine oxidase B (MAOB), an enzyme involved in dopamine metabolism, remains unexplored. In this study, an rG4 located in the MAOB mRNA’s 5′UTR was identified, and ways to either stabilize or reprogram this rG4 were explored. The translation inhibitory role of the rG4 was demonstrated both <i>in vitro</i> and <i>in cellulo</i> and was shown to be further accentuated in the presence of the PhenDC3 ligand. As an alternative to ligands, which cannot specifically stabilize only one G4, the MOAB rG4 was reprogrammed with G-rich antisense oligonucleotides (G-ASOs) from a two-quartets to three-quartets G4. The G-ASOs, either unmodified DNA or 2′OMe, were shown to both induce a new rG4 folding through intermolecular interactions and to specifically reduce the translation of MAOB both <i>in vitro</i> and <i>in cellulo</i>. These findings propose a targeted approach with which to modulate rG4 structures for therapeutics, suggesting that rG4 folding, when stabilized by G-ASOs, could regulate protein synthesis and even potentially alleviate PD symptoms by reducing MAOB activity. This approach opens new avenues as it could be used to reduce the expression of many therapeutic protein targets.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"403–414 403–414"},"PeriodicalIF":3.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering the Role of Distal Regions in PDK1 Allosteric Activation","authors":"Nagaraju Mulpuri,&nbsp;Xin-Qiu Yao and Donald Hamelberg*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0002510.1021/acsbiomedchemau.5c00025","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00025https://doi.org/10.1021/acsbiomedchemau.5c00025","url":null,"abstract":"<p >Allosteric regulation is a pivotal mechanism governing a wide array of cellular functions. Essential to this process is a flexible biomolecule allowing distant sites to interact through coordinated or sequential conformational shifts. Phosphoinositide-dependent kinase 1 (PDK1) possesses a conserved allosteric binding site, the PIF-pocket, which regulates the kinase’s ATP binding, catalytic activity, and substrate interactions. We elucidated the allosteric mechanisms of PDK1 by comparing conformational ensembles of the kinase bound with different small-molecule allosteric modulators in the PIF-pocket with that of the modulator-free kinase. Analysis of over 48 μs of simulations consistently shows that the allosteric modulators predominantly influence the conformational dynamics of specific distal regions from the PIF-pocket, driving allosteric activation. Furthermore, a recently developed advanced difference contact network community analysis is employed to elucidate allosteric communications. This approach integrates multiple conformational ensembles into a single community network, offering a valuable tool for future studies aimed at identifying function-related dynamics in proteins.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"299–309 299–309"},"PeriodicalIF":3.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering the Role of Distal Regions in PDK1 Allosteric Activation.","authors":"Nagaraju Mulpuri, Xin-Qiu Yao, Donald Hamelberg","doi":"10.1021/acsbiomedchemau.5c00025","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00025","url":null,"abstract":"<p><p>Allosteric regulation is a pivotal mechanism governing a wide array of cellular functions. Essential to this process is a flexible biomolecule allowing distant sites to interact through coordinated or sequential conformational shifts. Phosphoinositide-dependent kinase 1 (PDK1) possesses a conserved allosteric binding site, the PIF-pocket, which regulates the kinase's ATP binding, catalytic activity, and substrate interactions. We elucidated the allosteric mechanisms of PDK1 by comparing conformational ensembles of the kinase bound with different small-molecule allosteric modulators in the PIF-pocket with that of the modulator-free kinase. Analysis of over 48 μs of simulations consistently shows that the allosteric modulators predominantly influence the conformational dynamics of specific distal regions from the PIF-pocket, driving allosteric activation. Furthermore, a recently developed advanced difference contact network community analysis is employed to elucidate allosteric communications. This approach integrates multiple conformational ensembles into a single community network, offering a valuable tool for future studies aimed at identifying function-related dynamics in proteins.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"299-309"},"PeriodicalIF":3.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmentation of Antimicrobial Activity of Spiniferin by Introducing an Arginine Residue Toward Its Amino Terminus: A Possible Role of Cation−π Interaction","authors":"Jyotshana Saroj,&nbsp;Rahul Dev Verma,&nbsp;Sariyah Akhtar,&nbsp;Neeraj Kumar Verma,&nbsp;Arvind Gupta,&nbsp;Arsh Tripathi,&nbsp;Juhi Sharma,&nbsp;Kalyan Mitra,&nbsp;Mohammad Imran Siddiqi and Jimut Kanti Ghosh*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0011910.1021/acsbiomedchemau.4c00119","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00119https://doi.org/10.1021/acsbiomedchemau.4c00119","url":null,"abstract":"<p >Spiniferin is a 13-mer scorpion-origin antimicrobial peptide having poor antimicrobial activity. To augment Spiniferin’s antimicrobial activity, we enhanced its net positive charge by replacing a glutamic acid residue with an arginine residue toward its amino terminus. We envisaged that a cation−π interaction could be introduced between this arginine residue and the tryptophan residue located near the middle of Spiniferin. This cation−π interaction could promote stronger interaction of the peptide with a negatively charged bacterial membranes, resulting in its increased antimicrobial activity. Though glutamic acid-to-arginine substitution [Spiniferin(E4R)] enhanced both the antimicrobial and toxic properties of Spiniferin, the same replacement with a <span>d</span>-arginine residue [Spiniferin(E4dR)] significantly enhanced its antimicrobial activity against selected Gram-negative/positive bacteria and a MRSA strain while maintaining low hemolytic/cytotoxic properties. Interestingly, Spiniferin(E4dR) analogs, with its aromatic-tryptophan residue substituted with an aromatic phenylalanine or an aliphatic valine residue, and its <span>d</span>-arginine residue replaced with a <span>d</span>-lysine residue, showed much lesser antibacterial activity than Spiniferin(E4dR) or Spiniferin(E4R). The results indicated a crucial role of the tryptophan and <span>l</span>-/<span>d</span>-arginine combination in augmenting the antimicrobial activity of Spiniferin analogs, Spiniferin(E4R) and Spiniferin(E4dR). Spiniferin(E4dR) showed bactericidal properties against selected Gram-positive/negative bacteria. It permeabilized bacterial membranes and induced damages in bacterial membrane organization, suggesting that the bacterial plasma membrane is its target for exhibiting antimicrobial activity. Further, Spiniferin(E4dR) in the intravenous route demonstrated the survival of <i>E. coli</i> ATCC 25922-infected mice and the clearance of bacteria from the visceral organs of these mice. Computational studies showed the requisite distance between the arginine’s cationic side chain and the π-electron site of the tryptophan residue for a possible intramolecular cation−π interaction in Spiniferin(E4dR)/Spiniferin(E4R).</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"387–402 387–402"},"PeriodicalIF":3.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmentation of Antimicrobial Activity of Spiniferin by Introducing an Arginine Residue Toward Its Amino Terminus: A Possible Role of Cation-π Interaction.","authors":"Jyotshana Saroj, Rahul Dev Verma, Sariyah Akhtar, Neeraj Kumar Verma, Arvind Gupta, Arsh Tripathi, Juhi Sharma, Kalyan Mitra, Mohammad Imran Siddiqi, Jimut Kanti Ghosh","doi":"10.1021/acsbiomedchemau.4c00119","DOIUrl":"10.1021/acsbiomedchemau.4c00119","url":null,"abstract":"<p><p>Spiniferin is a 13-mer scorpion-origin antimicrobial peptide having poor antimicrobial activity. To augment Spiniferin's antimicrobial activity, we enhanced its net positive charge by replacing a glutamic acid residue with an arginine residue toward its amino terminus. We envisaged that a cation-π interaction could be introduced between this arginine residue and the tryptophan residue located near the middle of Spiniferin. This cation-π interaction could promote stronger interaction of the peptide with a negatively charged bacterial membranes, resulting in its increased antimicrobial activity. Though glutamic acid-to-arginine substitution [Spiniferin-(E4R)] enhanced both the antimicrobial and toxic properties of Spiniferin, the same replacement with a d-arginine residue [Spiniferin-(E4dR)] significantly enhanced its antimicrobial activity against selected Gram-negative/positive bacteria and a MRSA strain while maintaining low hemolytic/cytotoxic properties. Interestingly, Spiniferin-(E4dR) analogs, with its aromatic-tryptophan residue substituted with an aromatic phenylalanine or an aliphatic valine residue, and its d-arginine residue replaced with a d-lysine residue, showed much lesser antibacterial activity than Spiniferin-(E4dR) or Spiniferin-(E4R). The results indicated a crucial role of the tryptophan and l-/d-arginine combination in augmenting the antimicrobial activity of Spiniferin analogs, Spiniferin-(E4R) and Spiniferin-(E4dR). Spiniferin-(E4dR) showed bactericidal properties against selected Gram-positive/negative bacteria. It permeabilized bacterial membranes and induced damages in bacterial membrane organization, suggesting that the bacterial plasma membrane is its target for exhibiting antimicrobial activity. Further, Spiniferin-(E4dR) in the intravenous route demonstrated the survival of E. coli ATCC 25922-infected mice and the clearance of bacteria from the visceral organs of these mice. Computational studies showed the requisite distance between the arginine's cationic side chain and the π-electron site of the tryptophan residue for a possible intramolecular cation-π interaction in Spiniferin-(E4dR)/Spiniferin-(E4R).</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"387-402"},"PeriodicalIF":3.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}