RESUMO
BACKGROUND: Human immunodeficiency virus (HIV) infection continues to pose a major global health challenge. HIV entry into host cells via membrane fusion mediated by the viral envelope glycoprotein gp120/gp41 is a key step in the HIV life cycle. CCR5, expressed on CD4+ T cells and macrophages, acts as a coreceptor facilitating HIV-1 entry. The CCR5 antagonist maraviroc is used to treat HIV infection. However, it can cause adverse effects and has limitations such as only inhibiting CCR5-tropic viruses. There remains a need to develop alternative CCR5 inhibitors with improved safety profiles. PROBLEM STATEMENT: Natural products may offer advantages over synthetic inhibitors including higher bioavailability, binding affinity, effectiveness, lower toxicity, and molecular diversity. However, screening the vast chemical space of natural compounds to identify novel CCR5 inhibitors presents challenges. This study aimed to address this gap through a hybrid ligand-based pharmacophore modeling and molecular docking approach to virtually screen large natural product databases. METHODS: A reliable pharmacophore model was developed based on 311 known CCR5 antagonists and validated against an external data set. Five natural product databases containing over 306,000 compounds were filtered based on drug-likeness rules. The validated pharmacophore model screened the databases to identify 611 hits. Key residues of the CCR5 receptor crystal structure were identified for docking. The top hits were docked, and interactions were analyzed. Molecular dynamics simulations were conducted to examine complex stability. Computational prediction evaluated pharmacokinetic properties. RESULTS: Three compounds exhibited similar interactions and binding energies to maraviroc. MD simulations demonstrated complex stability comparable to maraviroc. One compound showed optimal predicted absorption, minimal metabolism, and a lower likelihood of interactions than maraviroc. CONCLUSION: This computational screening workflow identified three natural compounds with promising CCR5 inhibition and favorable pharmacokinetic profiles. One compound emerged as a lead based on bioavailability potential and minimal interaction risk. These findings present opportunities for developing alternative CCR5 antagonists and warrant further experimental investigation. Overall, the hybrid virtual screening approach proved effective for mining large natural product spaces to discover novel molecular entities with drug-like properties.
Assuntos
Produtos Biológicos , Antagonistas dos Receptores CCR5 , HIV-1 , Receptores CCR5 , Humanos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Maraviroc/química , Maraviroc/farmacologia , Simulação de Acoplamento Molecular , Receptores CCR5/metabolismo , Receptores CCR5/químicaRESUMO
The CC chemokine receptor 5 (CCR5) serves a pivotal role in human immunodeficiency virus 1 (HIV-1) infection by acting as a co-receptor and facilitating the binding of the viral envelope glycoprotein (env). Maraviroc (MVC), a Food and Drug Administration-approved monocarboxylic acid amide, is one of the CCR5 inhibitors employed in HIV treatment. Despite the existence of approved drugs, the emergence of drug resistance underscores the necessity for novel compounds to combat resistance and enhance therapeutic efficacy. In this study, CB-0821, identified from the ChemBridge library, emerged as a promising CCR5 inhibitor. Molecular dynamics simulations indicate comparable dynamic properties for CB-0821 and MVC. In silico comparisons with other CCR5 inhibitors emphasize CB-0821's superior binding affinity, positioning it as a potential lead compound. Evaluations of the dissociation constant (Ki) and absorption, distribution, metabolism, and excretion predictions suggest CB-0821 as a well-tolerated drug. Furthermore, the dose-dependent inhibition of CCR5 by CB-0821 in Peripheral blood mononuclear cells (PBMCs) (ranging from 10 to 200 nM) demonstrates efficacy, coupled with nontoxicity to Vero cells at concentrations up to 500 nM. These results underscore the potential of CB-0821 in HIV antiviral therapy, calling for additional preclinical validations before advancing to clinical considerations.
Assuntos
Fármacos Anti-HIV , Antagonistas dos Receptores CCR5 , Receptores CCR5 , Humanos , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Receptores CCR5/metabolismo , Animais , HIV-1/efeitos dos fármacos , Chlorocebus aethiops , Simulação de Dinâmica Molecular , Células Vero , Maraviroc/farmacologia , Maraviroc/química , Relação Dose-Resposta a Droga , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismoRESUMO
Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 µM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 µM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.
Assuntos
Antagonistas dos Receptores CCR5 , AVC Isquêmico , Neuroblastoma , Acidente Vascular Cerebral , Animais , Humanos , Camundongos , AVC Isquêmico/tratamento farmacológico , Maraviroc/uso terapêutico , Maraviroc/farmacologia , Simulação de Acoplamento Molecular , Receptores CCR5/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologiaRESUMO
The large number of pathologies that position CCR5 as a central molecular determinant substantiates the studies aimed at understanding receptor-ligand interactions, as well as the development of compounds that efficiently block this receptor. This perspective focuses on CCR5 antagonism as the preferred landscape for therapeutic intervention, thus the receptor active site occupancy by known antagonists of different origins is overviewed. CCL5 is a natural agonist ligand for CCR5 and an extensively studied scaffold for CCR5 antagonists production through chemokine N-terminus modification. A retrospective 3D modeling analysis on recently developed CCL5 mutants and their contribution to enhanced anti-HIV-1 activity is reported here. These results allow us to prospect the development of conceptually novel amino acid substitutions outside the CCL5 N-terminus hotspot. CCR5 interaction improvement in regions distal to the chemokine N-terminus, as well as the stabilization of the chemokine hydrophobic core are strategies that influence binding affinity and stability beyond the agonist/antagonist dualism. Furthermore, the development of allosteric antagonists topologically remote from the orthosteric site (e.g., intracellular or membrane-embedded) is an intriguing new avenue in GPCR druggability and thus a conceivable novel direction for CCR5 blockade. Ultimately, the three-dimensional structure elucidation of the interaction between various ligands and CCR5 helps illuminate the active site occupancy and mechanism of action.
Assuntos
Antagonistas dos Receptores CCR5/farmacologia , Quimiocina CCL5/química , HIV-1/fisiologia , Modelos Moleculares , Receptores CCR5/química , Animais , Antagonistas dos Receptores CCR5/química , Quimiocina CCL5/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Ligantes , Ligação Proteica , Receptores CCR5/metabolismoRESUMO
C-C chemokine receptor 5 (CCR5), which is part of the chemokine receptor family, is a member of the G protein-coupled receptor superfamily. The interactions of CCR5 with HIV-1 during viral entry position it as an effective therapeutic target for designing potent antiviral therapies. The small-molecule Maraviroc was approved by the FDA as a CCR5 drug in 2007, while clinical trials failure has characterised many of the other CCR5 inhibitors. Thus, the continual identification of potential CCR5 inhibitors is, therefore, warranted. In this study, a structure-based discovery approach has been utilised to screen and retrieved novel potential CCR5 inhibitors from the Asinex antiviral compound (â¼ 8,722) database. Explicit lipid-bilayer molecular dynamics simulation, in silico physicochemical and pharmacokinetic analyses, were further performed for the top compounds. A total of 23 structurally diverse compounds with binding scores higher than Maraviroc were selected. Subsequent molecular dynamics (MD) simulations analysis of the top four compounds LAS 51495192, BDB 26405401, BDB 26419079, and LAS 34154543, maintained stability at the CCR5 binding site. Furthermore, these compounds made pertinent interactions with CCR5 residues critical for the HIV-1 gp120-V3 loop binding such as Trp86, Tyr89, Phe109, Tyr108, Glu283 and Tyr251. Additionally, the predicted in silico physicochemical and pharmacokinetic descriptors of the selected compounds were within the acceptable range for drug-likeness. The results suggest positive indications that the identified molecules may represent promising CCR5 entry inhibitors. Further structural optimisations and biochemical testing of the proposed compounds may assist in the discovery of effective HIV-1 therapy.Communicated by Ramaswamy H. Sarma.
Assuntos
Inibidores da Fusão de HIV , Infecções por HIV , HIV-1 , Humanos , Maraviroc/farmacologia , Maraviroc/metabolismo , Maraviroc/uso terapêutico , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/uso terapêutico , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/uso terapêutico , Cicloexanos/farmacologia , Cicloexanos/química , Triazóis/farmacologia , Triazóis/química , Inibidores da Fusão de HIV/farmacologia , Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/uso terapêutico , Receptores CCR5/química , Receptores CCR5/metabolismo , Receptores CCR5/uso terapêutico , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/tratamento farmacológicoRESUMO
Previous studies have reported the stepwise nature of human immunodeficiency virus type 1 (HIV-1) entry and the pivotal role of coreceptor CCR5 and the gp41 N-terminal heptad repeat (NHR) region in this event. With this in mind, we herein report a dual-targeted drug compound featuring bifunctional entry inhibitors, consisting of a piperidine-4-carboxamide-based CCR5 antagonist, TAK-220, and a gp41 NHR-targeting fusion-inhibitory peptide, C34. The resultant chimeras were constructed by linking both pharmacophores with a polyethylene glycol spacer. One chimera, CP12TAK, exhibited exceptionally potent antiviral activity, about 40- and 306-fold over that of its parent inhibitors, C34 and TAK-220, respectively. In addition to R5-tropic viruses, CP12TAK also strongly inhibited infection of X4-tropic HIV-1 strains. These data are promising for the further development of CP12TAK as a new anti-HIV-1 drug. Results show that this strategy could be extended to the design of therapies against infection of other enveloped viruses.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Desenho de Fármacos , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Receptores CCR5/metabolismo , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5/síntese química , Antagonistas dos Receptores CCR5/química , Relação Dose-Resposta a Droga , Proteína gp41 do Envelope de HIV/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Internalização do Vírus/efeitos dos fármacosRESUMO
Current antiretroviral therapies against HIV involve the usage of at least two drugs that target different stages of HIV life cycle. However, potential drug interactions and side effects pose a problem. A promising concept for complex disease treatment is 'one molecule-multiple target' approach to overcome undesired effects of multiple drugs. Additionally, it is beneficial to consider drug re-purposing due to the cost of taking a drug into the market. Taking these into account, here potential anti-HIV compounds are suggested by virtually screening small approved drug molecules and clinical candidates. Initially, binary QSAR models are used to predict the therapeutic activity of around 7900 compounds against HIV and to predict the toxicity of molecules with high therapeutic activities. Selected compounds are considered for molecular docking studies against two targets, HIV-1 protease enzyme, and chemokine co-receptor CCR5. The top docking poses for all 549 molecules are then subjected to short (1â ns) individual molecular dynamics (MD) simulations and they are ranked based on their calculated relative binding free energies. Finally, 25 molecules are selected for long (200â ns) MD simulations, and 5 molecules are suggested as promising multi-target HIV agents. The results of this study may open new avenues for the designing of new dual HIV-1 inhibitor scaffolds.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Protease de HIV/química , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Humanos , Ligação Proteica , Receptores CCR5/química , Bibliotecas de Moléculas PequenasRESUMO
The first step for the HIV-1 virus infecting host cell is bound with the CCR5 chemokine receptor. A set of allosteric inhibitors of oximino-piperidino-piperidine antagonists for CCR5 chemokine receptor was discovered. However, the allosteric mechanism of these inhibitors is still unsolved. Therefore, residue-level dynamics correlation network combining with on molecular dynamics simulation was used to investigate the allosteric mechanism. The dynamics correlation network of bound CCR5 is significantly different from that of free CCR5. The community of the most active complex suggests that the allosteric information can freely transfer from the allosteric site to the effector site of the second extracellular loop, while the information transfers bottleneck for the less active one. Here, a hypothesis was proposed that "binding-induced allosteric mechanism" was used to reveal the allosteric regulation of antagonists and the network perturbation confirmed it. Finally, the shortest path algorithm was used to identify the possible allosteric pathway with Gly173-Lys171-Thr177-Tyr89-LIG which was evaluated by the network perturbation of key residue. Furthermore, the efficiency of allostery for the most active system is the highest among these antagonist complexes. The strategy targeting the allosteric pathway can be used to design novel inhibitors of HIV-1 virus.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5/química , Oximas/química , Piperidinas/química , Receptores CCR5/metabolismo , Sítio Alostérico , Sequência de Aminoácidos , Fármacos Anti-HIV/metabolismo , Antagonistas dos Receptores CCR5/metabolismo , Bases de Dados de Proteínas , Desenho de Fármacos , Infecções por HIV/metabolismo , Humanos , Simulação de Dinâmica Molecular , Conformação ProteicaRESUMO
Microbicides based on hydrogel have become an effective way to prevent the HIV replication and transmission because of their convenience and prolonging drug release. In this study, a hybrid thermo-sensitive hydrogel constituted by nanosized layered double hydroxides and poloxamer 407 (P407) was constructed and co-loaded with both hydrophobic and hydrophilic drug. The LDH-P407 hydrogel could achieve sol-gel transition at body temperature. The in vivo experiment showed that LDH-P407 hydrogel can achieve controlled release of theaflavin and Nile red (hydrophobic drug model) into blood by vaginal drug delivery, meanwhile the hydrogel showed barely mucosal irritation. In addition, ex vivo experiment showed that the nifeviroc-loaded LDH-P407 hydrogel was able to specifically bind co-receptor CCR5 of DCs cells. Therefore, the LDH-P407 hydrogel would be a promising carrier for intravaginal delivery of anti-HIV drugs.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Portadores de Fármacos/química , Hidrogéis/química , Hidróxidos/química , Temperatura , Administração Intravaginal , Animais , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5/administração & dosagem , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Portadores de Fármacos/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Hidróxidos/farmacocinética , Poloxâmero/química , Coelhos , Reologia , Distribuição TecidualRESUMO
CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50 value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross-resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous efforts in developing new CCR5 inhibitors with unique binding profiles is necessary.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Receptores CCR5/metabolismo , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/uso terapêutico , Sítios de Ligação/efeitos dos fármacos , Buffy Coat/citologia , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Células CHO , Linhagem Celular , Cricetulus , Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/fisiologia , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Concentração Inibidora 50 , Maraviroc/farmacologia , Maraviroc/uso terapêutico , Simulação de Acoplamento Molecular , Cultura Primária de Células , Receptores CCR5/ultraestrutura , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy.
Assuntos
Fármacos Anti-HIV/química , Infecções por HIV/tratamento farmacológico , Receptores CCR5/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Fármacos Anti-HIV/uso terapêutico , Benzilaminas , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/uso terapêutico , Ciclamos , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Maraviroc/química , Maraviroc/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Receptores CCR5/genética , Receptores CXCR4/genéticaRESUMO
Marine micro-organisms have been proven to be excellent sources of bioactive compounds against HIV-1. Several natural products obtained from marine-derived Aspergillus fungi were screened for their activities to inhibit HIV-1 infection. Penicillixanthone A (PXA), a natural xanthone dimer from jellyfish-derived fungus Aspergillus fumigates, displayed potent anti-HIV-1 activity by inhibiting infection against CCR5-tropic HIV-1 SF162 and CXCR4-tropic HIV-1 NL4-3, with IC50 of 0.36 and 0.26 µM, respectively. Molecular docking study was conducted to understand the possible binding mode of PXA with the CCR5/CXCR4. The results revealed that, the marine-derived PXA, as a CCR5/CXCR4 dual-coreceptor antagonist, presents a new type of potential lead product for the development of anti-HIV therapeutics.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Receptores CCR5/metabolismo , Xantonas/farmacologia , Fármacos Anti-HIV/química , Organismos Aquáticos/química , Aspergillus/química , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Simulação de Acoplamento Molecular , Receptores CCR5/química , Receptores CXCR4/antagonistas & inibidores , Xantonas/química , Xantonas/metabolismoRESUMO
CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 µM, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.
Assuntos
Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Diaminas/química , Diaminas/farmacologia , Desenho de Fármacos , Receptores CCR5/metabolismo , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/toxicidade , Antagonistas dos Receptores CCR5/toxicidade , Linhagem Celular , Diaminas/toxicidade , Humanos , Modelos Moleculares , Conformação Proteica , Receptores CCR5/químicaRESUMO
The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists.
Assuntos
Antirretrovirais/farmacologia , Antagonistas dos Receptores CCR5/farmacologia , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Receptores CCR5/metabolismo , Antirretrovirais/síntese química , Antirretrovirais/química , Antagonistas dos Receptores CCR5/síntese química , Antagonistas dos Receptores CCR5/química , Farmacorresistência Viral/efeitos dos fármacos , HumanosRESUMO
Principal component analysis (PCA), as a well-known multivariate data analysis and data reduction technique, is an important and useful algebraic tool in drug design and discovery. PCA, in a typical quantitative structure-activity relationship (QSAR) study, analyzes an original data matrix in which molecules are described by several intercorrelated quantitative dependent variables (molecular descriptors). Although extensively applied, there is disparity in the literature with respect to the applications of PCA in the QSAR studies. This study investigates the different applications of PCA in QSAR studies using a dataset including CCR5 inhibitors. The different types of preprocessing are used to compare the PCA performances. The use of PC plots in the exploratory investigation of matrix of descriptors is described. This work is also proved PCA analysis to be a powerful technique for exploring complex datasets in QSAR studies for identification of outliers. This study shows that PCA is able to easily apply to the pool of calculated structural descriptors and also the extracted information can be used to help decide upon an appropriate harder model for further analysis.
Assuntos
Antagonistas dos Receptores CCR5/química , Relação Quantitativa Estrutura-Atividade , Receptores CCR5/química , Algoritmos , Antagonistas dos Receptores CCR5/metabolismo , Desenho de Fármacos , Humanos , Análise de Componente Principal , Receptores CCR5/metabolismoRESUMO
CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.
Assuntos
Quimiocina CCL5/química , Proteína gp120 do Envelope de HIV/química , Infecções por HIV/imunologia , HIV-1/fisiologia , Modelos Moleculares , Mimetismo Molecular , Receptores CCR5/química , Animais , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Quimiocina CCL5/metabolismo , Clonagem Molecular , Cristalografia por Raios X , Cicloexanos/química , Cicloexanos/farmacologia , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , Humanos , Maraviroc , Ligação Proteica , Conformação Proteica , Receptores CCR5/metabolismo , Células Sf9 , Spodoptera , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Internalização do Vírus/efeitos dos fármacosRESUMO
Infections by the human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS), are still totaling an appalling 36.7 millions worldwide, with 1.1 million AIDS deaths/year and a similar number of yearly new infections. All this, in spite of the discovery of HIV-1 as the AIDS etiological agent more than 30 years ago and the introduction of an effective combinatorial antiretroviral therapy (cART), able to control disease progression, more than 20 years ago. Although very effective, current cART is plagued by the emergence of drug-resistant viral variants and most of the efforts in the development of novel direct-acting antiviral agents (DAAs) against HIV-1 have been devoted toward the fighting of resistance. In this review, rather than providing a detailed listing of all the drugs and the corresponding resistance mutations, we aim, through relevant examples, at presenting to the general reader the conceptual shift in the approaches that are being taken to overcome the viral resistance hurdle. From the classic 'running faster' strategy, based on the development of novel DAAs active against the mutant viruses selected by the previous drugs and/or presenting to the virus a high genetic barrier toward the development of resilience, to a 'jumping higher' approach, which looks at the cell, rather than the virus, as a source of valuable drug targets, in order to make the cellular environment non-permissive toward the replication of both wild-type and mutated viruses.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Desenho de Fármacos , Farmacorresistência Viral Múltipla , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Modelos Biológicos , Animais , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Quimioterapia Combinada/efeitos adversos , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , HIV-1/crescimento & desenvolvimento , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Proteínas do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Proteínas do Vírus da Imunodeficiência Humana/química , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , Mutação , Conformação Proteica , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Fenômenos Fisiológicos Virais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.
Assuntos
Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Dipeptidil Peptidase 4/metabolismo , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Receptores CCR5/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), plays a vital role in inflammatory responses to infection. Alterations in the expression of CCR5 have been correlated with disease progression in many types of cancers. The idea of using CCR5 as a target for therapeutic intervention has been demonstrated to prevent disease progression. To date, only a few compounds have been reported as CCR5 inhibitors. In this study, a series of CCR5 antagonists were used to construct pharmacophore models. Then the optimal model was utilized as a 3D query to identify novel chemical entities from structural databases. After refinement by molecular docking, drug-likeness analysis, molecular dynamics simulations (MDS) and binding free energy analysis, three potential inhibitors (25, 29 and 45) were identified. MD simulations suggested that the screened compounds retained the important common binding mode known for CCR5 inhibitors (maraviroc and nifeviroc), which occupied the bottom of a pocket and stabilized the conformation of CCR5. During the binding process, van der Waals interactions provided the substantial driving force. The most favorable contributions were from Tyr37, Trp86, Tyr89, Tyr108, Phe109, Phe112, Gln194, Thr195, Ile198, Trp248, Tyr251, Leu255, Thr259, Met279, Glu283 and Met287. The above results suggest that the hybrid strategy would provide a basis for rational drug design.
Assuntos
Antagonistas dos Receptores CCR5/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptores CCR5/química , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Desenho de Fármacos , Ligantes , Conformação Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection ultimately leading to acquired immunodeficiency syndrome (AIDS), remains a significant problem. CCR5 is a member of the chemokine receptor family that is utilized in the early stage of the replication cycle by the most commonly transmitted M-tropic strains of HIV-1. In this study, we developed 3D-QSAR models using CoMFA and CoMSIA methods on a series of 71 imidazolidinylpiperidinylbenzoic acid CCR5 antagonists, in order to better understand the substituent requirements and get more potent antagonists of CCR5. METHODS: The research of 3D-QSAR modeling of imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 (CCR5) antagonists was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). RESULTS: For this study, a dataset containing 71 imidazolidinyl-piperidinyl-benzoic acids was divided into a training set of 22 compounds and a test set of 49 compounds. The results obtained from the CoMFA/CoMSIA model exhibited a statistical significance r(2) of 0.996 (0.984) with an estimated standard error of 0.109 (0.209). CONCLUSION: Both CoMFA and CoMSIA models provided valuable insight into the structural requirements for improving the activity of then CCR5 antagonists.