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1.
Bioorg Med Chem ; 106: 117755, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38749343

RESUMO

Translesion synthesis (TLS) is a cellular mechanism through which actively replicating cells recruit specialized, low-fidelity DNA polymerases to damaged DNA to allow for replication past these lesions. REV1 is one of these TLS DNA polymerases that functions primarily as a scaffolding protein to organize the TLS heteroprotein complex and ensure replication occurs in the presence of DNA lesions. The C-Terminal domain of REV1 (REV1-CT) forms many protein-protein interactions (PPIs) with other TLS polymerases, making it essential for TLS function and a promising drug target for anti-cancer drug development. We utilized several lead identification strategies to identify various small molecules capable of disrupting the PPI between REV1-CT and the REV1 Interacting Regions (RIR) present in several other TLS polymerases. These lead compounds were profiled in several in vitro potency and PK assays to identify two scaffolds (1 and 6) as the most promising for further development. Both 1 and 6 synergized with cisplatin in a REV1-dependent fashion and demonstrated promising in vivo PK and toxicity profiles.


Assuntos
Nucleotidiltransferases , Bibliotecas de Moléculas Pequenas , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/metabolismo , Humanos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Animais , Relação Estrutura-Atividade , Ligação Proteica , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Dose-Resposta a Droga , DNA Polimerase Dirigida por DNA/metabolismo , Camundongos , Síntese de DNA Translesão
2.
Biochemistry ; 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35608245

RESUMO

DNA damage tolerance (DDT) pathways enable cells to cope with a variety of replication blocks that threaten their ability to complete DNA replication. Helicase-like transcription factor (HLTF) plays a central role in the error-free DDT pathway, template switching (TS), by serving as a ubiquitin ligase to polyubiquitinate the DNA sliding clamp PCNA, which promotes TS initiation. HLTF also serves as an ATP-dependent DNA translocase facilitating replication fork remodeling. The HIP116, Rad5p N-terminal (HIRAN) domain of HLTF specifically recognizes the unmodified 3'-end of single-stranded DNA (ssDNA) at stalled replication forks to promote fork regression. Several crystal structures of the HIRAN domain in complex with ssDNA have been reported; however, optimal ssDNA sequences for high-affinity binding with the domain have not been described. Here we elucidated DNA sequence preferences of HLTF HIRAN through systematic studies of its binding to ssDNA substrates using fluorescence polarization assays and a computational analysis of the ssDNA:HIRAN interaction. These studies reveal that the HLTF HIRAN domain preferentially recognizes a (T/C)TG sequence at the 3'-hydroxyl ssDNA end, which occurs in the CTG trinucleotide repeat (TNR) regions that are susceptible to expansion and deletion mutations identified in neuromuscular and neurodegenerative disorders. These findings support a role for HLTF in maintaining the stability of difficult to replicate TNR microsatellite regions.

3.
Molecules ; 26(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34577015

RESUMO

Translesion synthesis (TLS) is an error-prone DNA damage tolerance mechanism used by actively replicating cells to copy past DNA lesions and extend the primer strand. TLS ensures that cells continue replication in the presence of damaged DNA bases, albeit at the expense of an increased mutation rate. Recent studies have demonstrated a clear role for TLS in rescuing cancer cells treated with first-line genotoxic agents by allowing them to replicate and survive in the presence of chemotherapy-induced DNA lesions. The importance of TLS in both the initial response to chemotherapy and the long-term development of acquired resistance has allowed it to emerge as an interesting target for small molecule drug discovery. Proper TLS function is a complicated process involving a heteroprotein complex that mediates multiple attachment and switching steps through several protein-protein interactions (PPIs). In this review, we briefly describe the importance of TLS in cancer and provide an in-depth analysis of key TLS PPIs, focusing on key structural features at the PPI interface while also exploring the potential druggability of each key PPI.


Assuntos
Proteínas Nucleares , DNA , Reparo do DNA , Replicação do DNA , Humanos , Proteínas Nucleares/metabolismo , Ligação Proteica
4.
Virol J ; 17(1): 116, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32727587

RESUMO

BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating diseases affecting the pork industry globally. PRRS is caused by PRRS virus (PRRSV). Currently there are no effective treatments against this swine disease. METHODS: Through artificial intelligence molecular screening, we obtained a set of small molecule compounds predicted to target the scavenger receptor cysteine-rich domain 5 (SRCR5) of CD163, which is a cell surface receptor specific for PRRSV infection. These compounds were screened using a cell-based bimolecular fluorescence complementation (BiFC) assay, and the function of positive hit was further evaluated and validated by PRRSV-infection assay using porcine alveolar macrophages (PAMs). RESULTS: Using the BiFC assay, we identified one compound with previously unverified function, 4-Fluoro-2-methyl-N-[3-(3-morpholin-4-ylsulfonylanilino)quinoxalin-2-yl]benzenesulfonamide (designated here as B7), that significantly inhibits the interaction between the PRRSV glycoprotein (GP2a or GP4) and the CD163-SRCR5 domain. We further demonstrated that compound B7 inhibits PRRSV infection of PAMs, the primary target of PRRSV in a dose-dependent manner. B7 significantly inhibited the infection caused by both type I and type II PRRSV strains. Further comparison and functional evaluation of chemical compounds structurally related to B7 revealed that the 3-(morpholinosulfonyl)aniline moiety of B7 or the 3-(piperidinylsulfonyl)aniline moiety in a B7 analogue is important for the inhibitory function against PRRSV infection. CONCLUSIONS: Our study identified a novel strategy to potentially prevent PRRSV infection in pigs by blocking the PRRSV-CD163 interaction with small molecules.


Assuntos
Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Receptores de Superfície Celular/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Inteligência Artificial , Linhagem Celular , Células HEK293 , Humanos , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Domínios Proteicos , Suínos
5.
Molecules ; 25(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218364

RESUMO

While loss-of-function mutations in the ATRX gene have been implicated as a driving force for a variety of pediatric brain tumors, as well as pancreatic neuroendocrine tumors, the role of ATRX in gene regulation and oncogenic development is not well-characterized. The ADD domain of ATRX (ATRXADD) localizes the protein to chromatin by specifically binding to the histone H3 tail. This domain is also a primary region that is mutated in these cancers. The overall goal of our studies was to utilize a variety of techniques (experimental and computational) to probe the H3:ATRXADD protein-protein interaction (PPI). We developed two biochemical assays that can be utilized to study the interaction. These assays were utilized to experimentally validate and expand upon our previous computational results. We demonstrated that the three anchor points in the H3 tail (A1, K4, and K9) are all essential for high affinity binding and that disruption of more than one contact region will be required to develop a small molecule that disrupts the PPI. Our approach in this study could be applied to other domains of ATRX, as well as PPIs between other distinct proteins.


Assuntos
Histonas/química , Mapas de Interação de Proteínas , Bioensaio , Biotina/metabolismo , Calorimetria , Histonas/metabolismo , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Peptídeos/metabolismo , Ligação Proteica , Domínios Proteicos
6.
J Chem Inf Model ; 58(11): 2266-2277, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30289707

RESUMO

Translesion synthesis (TLS) is a mechanism of replication past damaged DNA through which multiple forms of human cancer survive and acquire resistance to first-line genotoxic chemotherapies. As such, TLS is emerging as a promising target for the development of a new class of anticancer agents. The C-terminal domain of the DNA polymerase Rev1 (Rev1-CT) mediates assembly of the functional TLS complex through protein-protein interactions (PPIs) with Rev1 interacting regions (RIRs) of several other TLS DNA polymerases. Utilizing structural knowledge of the Rev1-CT/RIR interface, we have identified the phenazopyridine scaffold as an inhibitor of this essential TLS PPI. We demonstrate direct binding of this scaffold to Rev1-CT, and the synthesis and evaluation of a small series of analogues have provided important structure-activity relationships for further development of this scaffold. Furthermore, we utilized the umbrella sampling method to predict the free energy of binding to Rev1-CT for each of our analogues. Binding energies calculated through umbrella sampling correlated well with experimentally determined IC50 values, validating this computational tool as a viable approach to predict the biological activity for inhibitors of the Rev1-CT/RIR PPI.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Proteínas Nucleares/metabolismo , Nucleotidiltransferases/metabolismo , Fenazopiridina/análogos & derivados , Fenazopiridina/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/química , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Termodinâmica
7.
Biochim Biophys Acta Gen Subj ; 1861(2): 168-177, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27825830

RESUMO

BACKGROUND: Multiple oxysterols (OHCs) have demonstrated the ability to act as agonists or antagonists of the hedgehog (Hh) signaling pathway, a developmental signaling pathway that has been implicated as a potential therapeutic target in a variety of human diseases. These OHCs are known to modulate Hh signaling through direct binding interactions with the N-terminal cysteine rich domain (CRD) of Smoothened, a key regulator of Hh signal transduction. METHODS: Homology modeling, molecular dynamics simulations, and MM/GBSA energy calculations were utilized to explore binding interactions between the OHC scaffold and the human Smoothened CRD. Follow-up cellular assays explored the in vitro activity of potential Hh pathway modulators. RESULTS: Structural features that govern key molecular interactions between the Smoothened CRD and the OHC scaffold were identified. Orientation of the iso-octyl side chain as well as the overall entropy of the OHC-CRD complex are important for determining activity against the Hh pathway. OHC 9, which was previously thought to be inactive because it was not an Hh agonist, was identified as an inhibitor of Hh signal transmission. CONCLUSIONS: Calculated MM/GBSA binding energies for OHCs in complex with the CRD of Smoothened correlate well with in vitro Hh modulatory activity. Compounds with high affinity stabilize Smoothened and are antagonists, whereas compounds with reduced affinity allow a conformational change in Smoothened that results in pathway activation. GENERAL SIGNIFICANCE: Computational modeling and molecular dynamics simulations can be used to predict whether a small molecule that binds the Smoothened CRD will be an agonist or antagonist of the pathway.


Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Oxisteróis/antagonistas & inibidores , Oxisteróis/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sequência de Aminoácidos , Cisteína/metabolismo , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica/fisiologia , Domínios Proteicos , Relação Estrutura-Atividade
8.
Mol Divers ; 19(4): 965-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26183841

RESUMO

Aurora kinases are sub-divided into Aurora A, Aurora B, and Aurora C kinases that are considered as prospective targets for a new class of anticancer drugs. In this work, a 4-D-QSAR model using an LQTA-QSAR approach with previously reported 31 derivatives of benzo[e]pyrimido[5,4 -b][1,4]diazepin -6(11H)-one as potent Aurora kinase A inhibitors has been created. Instead of single conformation, the conformational ensemble profile generated for each ligand by using trajectories and topology information retrieved from molecular dynamics simulations from GROMACS package were aligned and used for the calculation of intermolecular interaction energies at each grid point. The descriptors generated on the basis of these Coulomb and Lennard-Jones potentials as independent variables were used to perform a PLS analysis using biological activity as dependent variable. A good predictive model was generated with nine field descriptors and five latent variables. The model showed [Formula: see text]; [Formula: see text] and [Formula: see text]. This model was further validated systematically by using different validation parameters. This 4D-QSAR model gave valuable information to recognize features essential to adapt and develop novel potential Aurora kinase inhibitors.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinase A/química , Conformação Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade
9.
Mol Divers ; 18(4): 853-63, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25112687

RESUMO

Aurora kinases belong to family of highly conserved serine/threonine protein kinases that are involved in diverse cell cycle events and play a major role in regulation of cell division. Abnormal expression of Aurora kinases may lead to cancer; hence, these are considered as a potential target in cancer treatment. In this research article, we identified three novel Aurora A inhibitors using modern computational tools. A four-point common 3D pharmacophore hypothesis of Aurora A (AurA) inhibitors was developed using a diverse set of 55 thienopyrimidine derivatives. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out using atom-based alignment of diverse set of 55 molecules to evaluate the structure- activity relationships. Docking and 3D-QSAR studies were performed with the 3D structure of AurA to evaluate the generated pharmacophore. The pharmacophore model and 3D-QSAR results complemented the results of our docking study. The pharmacophore hypothesis, which yields the best results, was used to screen the Zinc 'clean drug-like' database. Various database filters such as 3D-arrangement of pharmacophoric features, predicted activity and binding interaction score were used to retrieve hits having potential AurA inhibition activity.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Conjuntos de Dados como Assunto , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade
10.
Molecules ; 19(4): 5243-65, 2014 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-24762964

RESUMO

Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated rcv2 value of 0.84 using three principal components and non-cross-validated r2 value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery.


Assuntos
Antagonistas dos Receptores CCR5 , Descoberta de Drogas , Inibidores da Fusão de HIV/química , Simulação de Acoplamento Molecular , Bibliotecas de Moléculas Pequenas/química , Sequência de Aminoácidos , Cicloexanos/química , Desenho de Fármacos , HIV-1/química , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Ensaios de Triagem em Larga Escala , Humanos , Interações Hidrofóbicas e Hidrofílicas , Maraviroc , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Análise de Componente Principal , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores CCR5/química , Termodinâmica , Triazóis/química , Interface Usuário-Computador , Internalização do Vírus/efeitos dos fármacos
11.
Mol Divers ; 16(2): 367-75, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22161148

RESUMO

The dopamine D(2) receptor is involved in the etiology of a number of disorders, such as Parkinson's disease, Huntington's Chorea, tardive dyskinesia and schizophrenia. Antagonism of D(2) receptors is implicated in the treatment of various psychiatric disorders. In order to understand essential structural features required for D(2) antagonism, this research article elaborates on the generation of a four-point 3D pharmacophore model which was extracted from a series of 45 novel 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazole derivatives. The best pharmacophore model generated consisted of four PRRR features: a positively charged group (P), and three aromatic rings (R). Based on the model generated, a statistically valid 3D-QSAR with good predictability (Q(2) = 0.756) was derived. For the validation of the pharmacophore hypothesis, active compounds were docked against the 3D structure of the D(2) receptor which was constructed through homology modeling. Further, the derived pharmacophore was used as a query to search the Zinc 'clean drug-like' database. Hits retrieved were passed progressively through filters, such as fitness score, predicted activity and docking scores. The resulting hits present new scaffolds with a strong potential for D(2) antagonist.


Assuntos
Antagonistas de Dopamina/química , Isoxazóis/química , Modelos Moleculares , Piperidinas/química , Relação Quantitativa Estrutura-Atividade , Antagonistas dos Receptores de Dopamina D2 , Humanos , Conformação Molecular
12.
Bioorg Med Chem Lett ; 21(8): 2419-24, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21397504

RESUMO

Monoamine oxidase-A (MAO-A) inhibitors are of particular importance in the treatment of depressive disorders. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported pyrrole based MAO-A inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated consisted of four features DHHR: a hydrogen bond donor (D), two hydrophobic groups (H) and an aromatic ring (R). Based on model generated, a statistically valid 3D-QSAR with good predictability was developed. Derived pharmacophore was used as a query to search Zinc 'clean drug-like' database. Hits retrieved were passed progressively through filters like fitness score, predicted activity and docking scores. The survived hits present new scaffolds with a potential for MAO-A inhibition.


Assuntos
Inibidores da Monoaminoxidase/química , Monoaminoxidase/química , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Bases de Dados Factuais , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Relação Quantitativa Estrutura-Atividade
13.
Expert Opin Investig Drugs ; 30(1): 13-24, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33179552

RESUMO

Introduction: Translesion synthesis (TLS) is a DNA damage tolerance mechanism that replaces the replicative DNA polymerase with a specialized, low-fidelity TLS DNA polymerase that can copy past DNA lesions during active replication. Recent studies have demonstrated a primary role for TLS in replicating past DNA lesions induced by first-line genotoxic agents, resulting in decreased efficacy and acquired chemoresistance. With this in mind, targeting TLS as a combination strategy with first-line genotoxic agents has emerged as a promising approach to develop a new class of anti-cancer adjuvant agents. Areas covered: In this review, we provide a brief background on TLS and its role in cancer. We also discuss the identification and development of inhibitors that target various TLS DNA polymerases or key protein-protein interactions (PPIs) in the TLS machinery. Expert opinion: TLS inhibitors have demonstrated initial promise; however, their continued study is essential to more fully understand the clinical potential of this emerging class of anti-cancer chemotherapeutics. It will be important to determine whether a specific protein involved in TLS is an optimal target. In addition, an expanded understanding of what current genotoxic chemotherapies synergize with TLS inhibitors will guide the clinical strategies for devising combination therapies.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/metabolismo , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia
14.
Mol Ther Oncolytics ; 20: 265-276, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33614910

RESUMO

The glioma-associated family of transcription factors (GLI) have emerged as a promising therapeutic target for a variety of human cancers. In particular, GLI1 plays a central role as a transcriptional regulator for multiple oncogenic signaling pathways, including the hedgehog (Hh) signaling pathway. We undertook a computational screening approach to identify small molecules that directly bind GLI1 for potential development as inhibitors of GLI-mediated transcription. Through these studies, we identified compound 1, which is an 8-hydroxyquinoline, as a high-affinity binder of GLI1. Compound 1 inhibits GLI1-mediated transcriptional activity in several Hh-dependent cellular models, including a primary model of murine medulloblastoma. We also performed a series of computational analyses to define more clearly the mechanism(s) through which 1 inhibits GLI1 function after binding. Our results strongly suggest that binding of 1 to GLI1 does not prevent GLI1/DNA binding nor disrupt the GLI1/DNA complex, but rather, it induces specific conformational changes in the overall complex that prevent proper GLI function. These results highlight the potential of this compound for further development as an anti-cancer agent that targets GLI1.

15.
Eur J Med Chem ; 163: 320-332, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529635

RESUMO

Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that π-π interactions between the compound and Smoothened play a key role in stabilizing the bound analogues.


Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Triazóis/farmacologia , Antifúngicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica , Receptor Smoothened/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêutico
16.
J Med Chem ; 62(8): 3873-3885, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30896941

RESUMO

The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.


Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Itraconazol/química , Triazóis/química , Animais , Sítios de Ligação , Linhagem Celular , Proliferação de Células , Desenho de Fármacos , Proteínas Hedgehog/metabolismo , Humanos , Itraconazol/metabolismo , Itraconazol/farmacologia , Camundongos , Simulação de Dinâmica Molecular , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
17.
Biochim Biophys Acta Gene Regul Mech ; 1861(6): 594-602, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29730439

RESUMO

The binding affinity between the histone 3 (H3) tail and the ADD domain of ATRX (ATRXADD) increases with the subsequent addition of methyl groups on lysine 9 on H3. To improve our understanding of how the difference in methylation state affects binding between H3 and the ATRXADD, we adopted a metadynamic approach to explore the recognition mechanism between the two proteins and identify the key intermolecular interactions that mediate this protein-peptide interaction (PPI). The non-methylated H3 peptide is recognized only by the PHD finger of ATRXADD while mono-, di-, and trimethylated H3 is recognized by both the PHD and GATA-like zinc finger of the domain. Furthermore, water molecules play an important role in orienting the lysine 9 anchor towards the GATA-like zinc finger, which results in stabilizing the lysine 9 binding pocket on ATRXADD. We compared our computational results against experimentally determined NMR and X-ray structures by demonstrating the RMSD, order parameter S2 and hydration number of the complex. The metadynamics data provide new insight into roles of water-bridges and the mechanisms through which K9 hydration stabilizes the H3K9me3:ATRXADD PPI, providing context for the high affinity demonstrated between this protein and peptide.


Assuntos
Histonas/química , Simulação de Dinâmica Molecular , Proteína Nuclear Ligada ao X/química , Histonas/metabolismo , Humanos , Metilação , Ligação Proteica , Domínios Proteicos , Proteína Nuclear Ligada ao X/metabolismo
18.
Eur J Med Chem ; 74: 358-65, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24486417

RESUMO

This article describes the design of biphenyl moiety linked with aryl piperazine and syntheses of fourteen 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanone derivatives along with their pharmacological evaluation for antipsychotic activity and computational studies including quantitative structure activity relationship (QSAR) and descriptor based similarity study. All compounds were found to exhibit considerable anti-dopaminergic and anti-serotonergic activity in behavioural models. Among all derivatives, compound 1-(biphenyl-4-yl)-2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethanone (3c) and 1-(biphenyl-4-yl)-2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]ethanone (3k) showed impressive antipsychotic profile with lower potency for catalepsy induction. These results were found to be sturdily matching with docking study in designing of compounds with homology model of human dopamine D2 receptor. Also the QSAR study strongly supports the obtained results.


Assuntos
Antipsicóticos/farmacologia , Piperazinas/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Quantitativa Estrutura-Atividade
19.
Med Chem ; 8(6): 1069-75, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22779792

RESUMO

A series of novel N,N-diphenyl-2-[4-(substituted phenyl)piperazin-1-yl]acetamides was designed, synthesized and evaluated for anti-dopaminergic activity, anti-serotonergic activity and catalepsy induction studies in mice as an approach to novel potential antipsychotic agent. Antipsychotic activity of these compounds in terms of blocking of dopaminergic transmission was evaluated by their ability to inhibit apomorphine induced climbing behavior in mice and antiserotonergic activity of synthesized compounds was assessed by studying inhibition of 5-HTP induced head twitches. All the synthesized compounds were found to exhibit anti-dopaminergic and anti-serotonergic activity in behavioral models. The compound 3f showed better antipsychotic potential among the different synthesized compounds. The descriptor based similarities study for blood brain permeation established a good similarity between the synthesized compounds with standard atypical antipsychotics.


Assuntos
Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Desenho de Fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Animais , Antipsicóticos/química , Antipsicóticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Catalepsia/tratamento farmacológico , Técnicas de Química Sintética , Humanos , Masculino , Camundongos , Piperazinas/química , Piperazinas/uso terapêutico
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