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1.
iScience ; 24(6): 102573, 2021 Jun 25.
Article in English | MEDLINE | ID: mdl-34142060

ABSTRACT

Unfolding followed by fibrillation of insulin even in the presence of various excipients grappled with restricted clinical application. Thus, there is an unmet need for better thermostable, nontoxic molecules to preserve bioactive insulin under varying physiochemical perturbations. In search of cross-amyloid inhibitors, prion-derived tetrapeptide library screening reveals a consensus V(X)YR motif for potential inhibition of insulin fibrillation. A tetrapeptide VYYR, isosequential to the ß2-strand of prion, effectively suppresses heat- and storage-induced insulin fibrillation and maintains insulin in a thermostable bioactive form conferring adequate glycemic control in mouse models of diabetes and impedes insulin amyloidoma formation. Besides elucidating the critical insulin-IS1 interaction (R4 of IS1 to the N24 insulin B-chain) by nuclear magnetic resonance spectroscopy, we further demonstrated non-canonical dimer-mediated conformational trapping mechanism for insulin stabilization. In this study, structural characterization and preclinical validation introduce a class of tetrapeptide toward developing thermostable therapeutically relevant insulin formulations.

2.
Sci Rep ; 9(1): 4073, 2019 03 11.
Article in English | MEDLINE | ID: mdl-30858542

ABSTRACT

Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.


Subject(s)
Diterpenes/pharmacology , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/genetics , Andrographis paniculata , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Blood Vessels/drug effects , Blood Vessels/metabolism , Carrier Proteins/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Collagen/pharmacology , Diterpenes/chemistry , Drug Combinations , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Laminin/pharmacology , Neoplasms/genetics , Neoplasms/pathology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Plant Extracts/chemistry , Protein Conformation/drug effects , Proteoglycans/pharmacology , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/chemistry , Vascular Endothelial Growth Factor Receptor-2/chemistry
3.
J Biomol Struct Dyn ; 37(5): 1282-1306, 2019 Mar.
Article in English | MEDLINE | ID: mdl-29578387

ABSTRACT

Alzheimer's disease (AD) is a multi-factorial disease, which can be simply outlined as an irreversible and progressive neurodegenerative disorder with an unclear root cause. It is a major cause of dementia in old aged people. In the present study, utilizing the structural and biological activity information of ligands for five important and mostly studied vital targets (i.e. cyclin-dependant kinase 5, ß-secretase, monoamine oxidase B, glycogen synthase kinase 3ß, acetylcholinesterase) that are believed to be effective against AD, we have developed five classification models using linear discriminant analysis (LDA) technique. Considering the importance of data curation, we have given more attention towards the chemical and biological data curation, which is a difficult task especially in case of big data-sets. Thus, to ease the curation process we have designed Konstanz Information Miner (KNIME) workflows, which are made available at http://teqip.jdvu.ac.in/QSAR_Tools/ . The developed models were appropriately validated based on the predictions for experiment derived data from test sets, as well as true external set compounds including known multi-target compounds. The domain of applicability for each classification model was checked based on a confidence estimation approach. Further, these validated models were employed for screening of natural compounds collected from the InterBioScreen natural database ( https://www.ibscreen.com/natural-compounds ). Further, the natural compounds that were categorized as 'actives' in at least two classification models out of five developed models were considered as multi-target leads, and these compounds were further screened using the drug-like filter, molecular docking technique and then thoroughly analyzed using molecular dynamics studies. Finally, the most potential multi-target natural compounds against AD are suggested.


Subject(s)
Biological Products/chemistry , Biological Products/pharmacology , Drug Discovery , Molecular Docking Simulation , Molecular Dynamics Simulation , Alzheimer Disease/drug therapy , Biomarkers , Databases, Genetic , Databases, Pharmaceutical , Drug Design , Humans , Ligands , ROC Curve , Workflow
4.
Oncotarget ; 8(66): 110234-110256, 2017 Dec 15.
Article in English | MEDLINE | ID: mdl-29299144

ABSTRACT

Discovery of anti-metastatic drugs is of immense clinical significance as metastasis is responsible for 90% of all cancer deaths. Here we report the inhibitory effect of a bis schiff base (M2) on cancer cell migration and invasion in vitro and in vivo. M2 has shown good solubility and permeability across the intestinal cell wall and hence can be classified as BCS (Biopharmaceutical classification system) class I. Microarray studies identified a long non coding intergenic RNA, LINC00273 as a novel molecular target of M2. We report that LINC00273 harbors a unique (4n-1) parallel G-Quadruplex structure in its promoter as validated by DMS footprint. M2 is proposed to stabilize this G-quadruplex structure resulting in the down-regulation of LINC00273 expression. Dual Luciferase reporter assay also suggests inhibition of LINC00273 promoter activity by M2. Involvement of this linc in metastasis is proven by siRNA and shRNA mediated knock down of LINC00273 in vitro and in vivo in nude mice which significantly decelerates cancer cell migration and invasion and also makes the cells unresponsive to TGF-ß's pro-metastatic effects. Furthermore, the real time expression of LINC00273 in thirty seven human clinical samples is found to be positively correlated with the histopathological staging of metastasis.

5.
ACS Omega ; 2(8): 4382-4397, 2017 Aug 31.
Article in English | MEDLINE | ID: mdl-30023722

ABSTRACT

Overexpression of c-MYC oncogene is associated with cancer pathology. Expression of c-MYC is regulated by the G-quadruplex structure formed in the G-rich segment of nuclease hypersensitive element (NHE III1), that is, "Pu27", which is localized in the promoter region. Ligand-induced stabilization of the Pu27 structure has been identified as a novel target for cancer therapeutics. Here, we have explored the library of synthetic compounds against the predefined binding site of Pu27. Three compounds were selected based on the docking analyses; they were further scrutinized using all atom molecular dynamics simulations in an explicit water model. Simulated trajectories were scrutinized for conformational stability and ligand binding free energy estimation; essential dynamic behavior was determined using principal component analysis. One of the molecules, "TPP (1-(3-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-2-hydroxypropyl)-4-carbamoylpiperidinium)", with the best results was considered for further evaluation. The theoretical observations are supported well by biophysical analysis using circular dichroism, isothermal titration calorimetry, and high-resolution NMR spectroscopy indicating association of TPP with Pu27. The in vitro studies were then translated into c-MYC overexpression in the T47D breast cancer cell line. Biological evaluation through the MTT assay, flow cytometric assay, RT-PCR, and reporter luciferase assay suggests that TPP downregulates the expression of c-MYC oncogene by arresting its promoter region. In silico and in vitro observations cumulatively suggest that the novel skeleton of TPP could be a potential anticancer agent by stabilizing the G-quadruplex formed in the Pu27 and consequently downregulating the expression of c-MYC oncogene. Derivation of new molecules on its skeleton may confer anticancer therapeutics for the next generation.

6.
Sci Rep ; 6: 32626, 2016 09 07.
Article in English | MEDLINE | ID: mdl-27601274

ABSTRACT

p53 preserves genomic integrity by restricting anomaly at the gene level. Till date, limited information is available for cytosol to nuclear shuttling of p53; except microtubule-based trafficking route, which utilizes minus-end directed motor dynein. The present study suggests that monomeric actin (G-actin) guides p53 traffic towards the nucleus. Histidine-tag pull-down assay using purified p53(1-393)-His and G-actin confirms direct physical association between p53 and monomeric G-actin. Co-immunoprecipitation data supports the same. Confocal imaging explores intense perinuclear colocalization between p53 and G-actin. To address atomistic details of the complex, constraint-based docked model of p53:G-actin complex was generated based on crystal structures. MD simulation reveals that p53 DNA-binding domain arrests very well the G-actin protein. Docking benchmark studies have been carried out for a known crystal structure, 1YCS (complex between p53DBD and BP2), which validates the docking protocol we adopted. Co-immunoprecipitation study using "hot-spot" p53 mutants suggested reduced G-actin association with cancer-associated p53 conformational mutants (R175H and R249S). Considering these findings, we hypothesized that point mutation in p53 structure, which diminishes p53:G-actin complexation results in mutant p53 altered subcellular localization. Our model suggests p53Arg249 form polar-contact with Arg357 of G-actin, which upon mutation, destabilizes p53:G-actin interaction and results in cytoplasmic retention of p53R249S.


Subject(s)
Actins/metabolism , Cell Nucleus/metabolism , Mutant Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Cell Line, Tumor , Cross-Linking Reagents/metabolism , Doxorubicin/pharmacology , Molecular Dynamics Simulation , Polymerization/drug effects , Protein Binding/drug effects , Protein Multimerization/drug effects , Protein Transport/drug effects , Rabbits , Subcellular Fractions/metabolism
7.
Apoptosis ; 21(10): 1106-24, 2016 10.
Article in English | MEDLINE | ID: mdl-27392939

ABSTRACT

The efficacy of cancer chemotherapeutics is limited by side effects resulting from narrow therapeutic windows between the anticancer activity of a drug and its cytotoxicity. Thus identification of small molecules that can selectively target cancer cells has gained major interest. Cancer cells under stress utilize the Unfolded protein response (UPR) as an effective cell adaptation mechanism. The purpose of the UPR is to balance the ER folding environment and calcium homeostasis under stress. If ER stress is prolonged, tumor cells undergo apoptosis. In the present study we demonstrated an 3,3'-(Arylmethylene)-bis-1H-indole (AMBI) derivative 3,3'-[(4-Methoxyphenyl) methylene]-bis-(5-bromo-1H-indole), named as Mephebrindole (MPB) as an effective anti-cancer agent in breast cancer cells. MPB disrupted calcium homeostasis in MCF7 cells which triggered ER stress development. Detailed evaluations revealed that mephebrindole by activating p38MAPK also regulated GRP78 and eIF2α/ATF4 downstream to promote apoptosis. Studies extended to in vivo allograft mice models revalidated its anti-carcinogenic property thus highlighting the role of MPB as an improved chemotherapeutic option.


Subject(s)
Activating Transcription Factor 4/metabolism , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Eukaryotic Initiation Factor-2/metabolism , Indoles/administration & dosage , Transcription Factor CHOP/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Activating Transcription Factor 4/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/physiopathology , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/physiopathology , Cell Line, Tumor , Endoplasmic Reticulum Chaperone BiP , Eukaryotic Initiation Factor-2/genetics , Female , Humans , Indoles/chemical synthesis , Indoles/chemistry , Mice , Receptor Cross-Talk/drug effects , Signal Transduction/drug effects , Transcription Factor CHOP/genetics , p38 Mitogen-Activated Protein Kinases/genetics
8.
J Med Chem ; 59(10): 5035-50, 2016 05 26.
Article in English | MEDLINE | ID: mdl-27058681

ABSTRACT

Accumulating evidence suggests that G-quadruplexes play vital roles in gene expression, DNA replication, and recombination. Three distinct promoters (PI, PII, and PIII) regulate human acetyl-CoA carboxylase 1 (ACC1) gene expression. In this study, we asked whether the G-rich sequences within the human ACC1 (PI and PII) promoters can form G-quadruplex structures and regulate normal DNA transactions. Using multiple complementary methods, we show that G-rich sequences of PI and PII promoters form intramolecular G-quadruplex structures and then establish unambiguously the topologies of these structures. Importantly, G-quadruplex formation in ACC1 gene promoter region blocks DNA replication and suppresses transcription, and this effect was further augmented by G-quadruplex stabilizing ligands. Altogether, these results are consistent with the notion that G-quadruplex structures exist within the human ACC1 gene promoter region, whose activity can be suppressed by G-quadruplex stabilizing ligands, thereby revealing a novel regulatory mechanism of ACC1 gene expression and as a possible therapeutic target.


Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Drug Discovery , G-Quadruplexes/drug effects , Nucleic Acid Conformation , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics , Transcription, Genetic/drug effects , Acetyl-CoA Carboxylase/metabolism , Dose-Response Relationship, Drug , HeLa Cells , Humans , Ligands , Molecular Structure , Nucleic Acid Conformation/drug effects , Structure-Activity Relationship , Transcription, Genetic/genetics , Tumor Cells, Cultured
9.
Mol Biosyst ; 12(1): 18-22, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26583504

ABSTRACT

A stable intermediate dimeric G-rich form as a precursor of tetrameric G-quadruplex structures has been detected via MALDI-TOF spectrometry. Molecular dynamics simulation offered detailed insights at the atomic level, assigning reverse Watson-Crick G-G base pairing (not Hoogsteen) in the G-rich dimer. In support of this, cisplatin formed a stable adduct by binding to the dimeric G-rich structure, eliminating the possibility of G-G Hoogsteen hydrogen bond formation.


Subject(s)
Base Pairing , G-Quadruplexes , Hydrogen Bonding , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Nucleic Acid Conformation , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
10.
Proc Natl Acad Sci U S A ; 112(26): E3374-83, 2015 Jun 30.
Article in English | MEDLINE | ID: mdl-26080397

ABSTRACT

Pre-mRNA splicing is a complex regulatory nexus modulated by various trans-factors and their posttranslational modifications to create a dynamic transcriptome through alternative splicing. Signal-induced phosphorylation and dephosphorylation of trans-factors are known to regulate alternative splicing. However, the role of other posttranslational modifications, such as deacetylation/acetylation, methylation, and ubiquitination, that could modulate alternative splicing in either a signal-dependent or -independent manner remain enigmatic. Here, we demonstrate that Scaffold/matrix-associated region-binding protein 1 (SMAR1) negatively regulates alternative splicing through histone deacetylase 6 (HDAC6)-mediated deacetylation of RNA-binding protein Sam68 (Src-associated substrate during mitosis of 68 kDa). SMAR1 is enriched in nuclear splicing speckles and associates with the snRNAs that are involved in splice site recognition. ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. We showed that endogenously, SMAR1 through HDAC6 maintains Sam68 in a deacetylated state. However, knockdown or ERK-mediated phosphorylation of SMAR1 releases the inhibitory SMAR1-HDAC6-Sam68 complex, facilitating Sam68 acetylation and alternative splicing. Furthermore, loss of heterozygosity at the Chr.16q24.3 locus in breast cancer cells, wherein the human homolog of SMAR1 (BANP) has been mapped, enhances Sam68 acetylation and CD44 variant exon inclusion. In addition, tail-vein injections in mice with human breast cancer MCF-7 cells depleted for SMAR1 showed increased CD44 variant exon inclusion and concomitant metastatic propensity, confirming the functional role of SMAR1 in regulation of alternative splicing. Thus, our results reveal the complex molecular mechanism underlying SMAR1-mediated signal-dependent and -independent regulation of alternative splicing via Sam68 deacetylation.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Alternative Splicing/physiology , Cell Cycle Proteins/physiology , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/physiology , Histone Deacetylases/metabolism , Nuclear Matrix/metabolism , Nuclear Proteins/physiology , RNA-Binding Proteins/metabolism , Acetylation , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cytoplasm/metabolism , DNA-Binding Proteins/genetics , Gene Knockdown Techniques , Histone Deacetylase 6 , Humans , Hyaluronan Receptors/genetics , MAP Kinase Signaling System , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Transport
11.
Biochemistry ; 54(13): 2249-2261, 2015 Apr 07.
Article in English | MEDLINE | ID: mdl-25785896

ABSTRACT

Molecular self-assembly, a phenomenon widely observed in nature, has been exploited through organic molecules, proteins, DNA, and peptides to study complex biological systems. These self-assembly systems may also be used in understanding the molecular and structural biology which can inspire the design and synthesis of increasingly complex biomaterials. Specifically, use of these building blocks to investigate protein folding and misfolding has been of particular value since it can provide tremendous insights into peptide aggregation related to a variety of protein misfolding diseases, or amyloid diseases (e.g., Alzheimer's disease, Parkinson's disease, type-II diabetes). Herein, the self-assembly of TK9, a nine-residue peptide of the extra membrane C-terminal tail of the SARS corona virus envelope, and its variants were characterized through biophysical, spectroscopic, and simulated studies, and it was confirmed that the structure of these peptides influences their aggregation propensity, hence, mimicking amyloid proteins. TK9, which forms a beta-sheet rich fibril, contains a key sequence motif that may be critical for beta-sheet formation, thus making it an interesting system to study amyloid fibrillation. TK9 aggregates were further examined through simulations to evaluate the possible intra- and interpeptide interactions at the molecular level. These self-assembly peptides can also serve as amyloid inhibitors through hydrophobic and electrophilic recognition interactions. Our results show that TK9 inhibits the fibrillation of hIAPP, a 37 amino acid peptide implicated in the pathology of type-II diabetes. Thus, biophysical and NMR experimental results have revealed a molecular level understanding of peptide folding events, as well as the inhibition of amyloid-protein aggregation are reported.


Subject(s)
Islet Amyloid Polypeptide/metabolism , Viral Envelope Proteins/chemistry , Amyloid/chemistry , Amyloid/metabolism , Circular Dichroism , Humans , Hydrophobic and Hydrophilic Interactions , Islet Amyloid Polypeptide/antagonists & inhibitors , Molecular Dynamics Simulation , Nuclear Magnetic Resonance, Biomolecular , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Protein Folding , Protein Structure, Secondary , Spectrometry, Fluorescence , Viral Envelope Proteins/metabolism , Viroporin Proteins
12.
Expert Opin Ther Targets ; 19(1): 13-23, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25363346

ABSTRACT

OBJECTIVE: PKCßII is a potential target for therapeutic intervention against pandemic diabetic complications. Present study probes the molecular interactions of PKCßII with its clinically important ligands, viz. ruboxistaurin, enzastaurin and co-crystallized ligand, 2-methyl-1H-indol-3-yl-BIM-1. RESEARCH DESIGN AND METHODS: The essentials of PKCßII-ligand interaction, crystal water-induced alterations in these interactions and key interacting flexible residues are analyzed. Computational methodologies, viz. molecular docking and molecular simulation coupled with molecular mechanics-Poisson-Boltzmann surface area and generalized born surface area (MM-PB[GB]SA) are employed. RESULTS: The structural changes in the presence and absence of crystal water molecules in PKCßII ATP binding site residues, and its interaction with bound ligand, are identified. Difference in interaction of selective and nonselective ligand with ATP binding site residues of PKCßII is reported. CONCLUSIONS: The study showed that the nonbonding interactions contribute significantly in PKCßII-ligand binding and presence of crystal water molecules affects the interactions. The findings of present work may integrate the new aspects in the drug design process of PKCßII inhibitors.


Subject(s)
Indoles/chemistry , Maleimides/chemistry , Protein Kinase C beta/chemistry , Protein Kinase Inhibitors/chemistry , Water/chemistry , Adenosine Triphosphate/chemistry , Binding Sites , Crystallization , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Kinase C beta/antagonists & inhibitors
13.
Mol Divers ; 17(1): 111-22, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23325357

ABSTRACT

Parkinson's disease (PD) is a degenerative disorder of the CNS, characterized by cerebral depletion of dopamine (DA), hence one of the approaches to delay the depletion of DA is to inhibit its oxidative deamination. Monoamine oxidases (MAO) carry out the oxidative deamination of monoamines like DA. These are intracellular enzymes, located on the outer mitochondrial membrane. MAO-A and MAO-B are the two subtypes of which MAO-B is the most predominant enzyme and is commonly found in the brain. Inhibition of the MAO-B enzyme boosts the effect of both endogenous and exogenous DA. In this study, we have carried out crystal structure analysis and structure-based design of MAO-B inhibitors. We also performed molecular dynamics, flexible docking, induced-fit docking and ADME prediction of the newly designed compounds.


Subject(s)
Monoamine Oxidase Inhibitors , Monoamine Oxidase , Parkinson Disease/drug therapy , Brain/enzymology , Brain/metabolism , Drug Design , Molecular Docking Simulation , Molecular Dynamics Simulation , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Monoamine Oxidase/ultrastructure , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology
14.
Expert Opin Ther Targets ; 16(3): 325-44, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22404224

ABSTRACT

INTRODUCTION: PKC-ßII is a conventional isoform of PKC. It is overexpressed in hyperglycemic conditions and is known to trigger various diabetic complications, mainly cardiovascular complications and to a certain extent nephropathy, neuropathy, retinopathy etc. Selective inhibition of this enzyme will be one of the favorable approaches to treat diabetes-mellitus-related complications. Due to high sequence similarities among PKC isoforms, selective inhibition of PKC-ßII is difficult and yet to be achieved successfully. AREAS COVERED: This review discusses the studies carried out in various aspects of PKC-ßII. The biological aspects, crystal structure data, structure­activity relationship study (SAR) and in silico studies related to PKC-ßII such as homology modeling, molecular docking, molecular dynamics, quantitative structure­activity relationship (QSAR) studies and pharmacophore modeling etc. are summarized. EXPERT OPINION: PKC-ßII is a potential target for treating diabetes-related complications. Selective inhibitors of this enzyme are under clinical trials but to date, success has not been achieved. Thus, extensive research is essential in this direction; the contribution of in silico tools in designing and optimizing selective inhibitors of PKC-ßII is valuable.


Subject(s)
Diabetes Complications/metabolism , Protein Kinase C/metabolism , Animals , Humans , Models, Molecular , Protein Conformation , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/chemistry , Protein Kinase C beta , Structure-Activity Relationship
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