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1.
Int J Mol Sci ; 25(15)2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-39125808

RESUMO

Multifactorial diseases demand therapeutics that can modulate multiple targets for enhanced safety and efficacy, yet the clinical approval of multitarget drugs remains rare. The integration of machine learning (ML) and deep learning (DL) in drug discovery has revolutionized virtual screening. This study investigates the synergy between ML/DL methodologies, molecular representations, and data augmentation strategies. Notably, we found that SVM can match or even surpass the performance of state-of-the-art DL methods. However, conventional data augmentation often involves a trade-off between the true positive rate and false positive rate. To address this, we introduce Negative-Augmented PU-bagging (NAPU-bagging) SVM, a novel semi-supervised learning framework. By leveraging ensemble SVM classifiers trained on resampled bags containing positive, negative, and unlabeled data, our approach is capable of managing false positive rates while maintaining high recall rates. We applied this method to the identification of multitarget-directed ligands (MTDLs), where high recall rates are critical for compiling a list of interaction candidate compounds. Case studies demonstrate that NAPU-bagging SVM can identify structurally novel MTDL hits for ALK-EGFR with favorable docking scores and binding modes, as well as pan-agonists for dopamine receptors. The NAPU-bagging SVM methodology should serve as a promising avenue to virtual screening, especially for the discovery of MTDLs.


Assuntos
Descoberta de Drogas , Descoberta de Drogas/métodos , Humanos , Simulação de Acoplamento Molecular , Ligantes , Máquina de Vetores de Suporte , Aprendizado Profundo , Aprendizado de Máquina Supervisionado , Aprendizado de Máquina
2.
Biochem Biophys Res Commun ; 679: 116-121, 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37683456

RESUMO

Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism. Using a high-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay, we have identified that the immunosuppressor KRP203/Mocravimod induces a significant perturbation in phosphoinositide metabolism in U87MG glioblastoma cells. Despite high sequence similarity of PI5P4K and PI4K isozymes, in vitro kinase assays showed that KRP203 activates some (e.g., PI5P4Kα, PI4KIIß) while inhibiting other phosphoinositide kinases (e.g., PI5P4Kß, γ, PI4KIIα, class I PI3K-p110α, δ, γ). Furthermore, KRP203 enhances PI3P5K/PIKFYVE's substrate selectivity for phosphatidylinositol (PI) while preserving its selectivity for PI(3)P. At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3,5)P2, and PI(3,4,5)P3 levels in U87MG cells. Collectively, the finding of multimodal activity of KRP203 towards multi-phosphoinositide kinases may open a novel basis to modulate cellular processes, potentially leading to more effective treatments for diseases associated with phosphoinositide signaling pathways.

4.
Bioorg Chem ; 131: 106335, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36603243

RESUMO

Currently, the development of effective analgesic drugs with few side effects remains a great challenge. Studies have suggested that multi-target drug treatments show high efficacy and reduced side effects compared to single-target drug therapies. In this work, we designed and synthesized two series of novel MOR/TRPV1 dual active ligands in which the phenylpiperidine group or the N-phenyl-N-(piperidin-4-yl) propionamide group as the MOR pharmacophore was fused to the benzylpiperazinyl urea-based TRPV1 pharmacophore. In particular, compound 5a exhibited promising dual pharmacological activity for MOR (EC50 = 53.7 nM) and TRPV1 (IC50 = 32.9 nM) in vitro. In formalin tests, compound 5a showed potent, dose-dependent in vivo analgesic activity in both the 1st and 2nd phases. Gratifyingly, compound 5a did not cause the side effects of hyperthermia and analgesic tolerance. Consistent with its in vitro activity, compound 5a also simultaneously agonized MOR and antagonized TRPV1 in vivo. Further studies on compound 5a showed acceptable pharmacokinetic properties and brain permeability. Furthermore, molecular docking studies showed that compound 5a tightly bound to the active pockets of hMOR and hTRPV1, respectively. Overall, this work shows the promise in discovering new analgesic treatments through the strategy of simultaneously targeting MOR and TRPV1 with a single molecule.


Assuntos
Analgésicos Opioides , Manejo da Dor , Canais de Cátion TRPV , Analgésicos Opioides/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Canais de Cátion TRPV/metabolismo
5.
Biomolecules ; 12(10)2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36291595

RESUMO

Alzheimer's disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aß) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aß oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer's disease, by targeting both neuroinflammation and neurodegeneration.


Assuntos
Doença de Alzheimer , Animais , Camundongos , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Catepsina G/metabolismo , Azul Tripano , Proteínas de Ligação ao Cálcio
6.
J Enzyme Inhib Med Chem ; 37(1): 2348-2356, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36050834

RESUMO

Multitarget drugs are a promising therapeutic approach against Alzheimer's disease. In this work, a new family of 5-substituted indazole derivatives with a multitarget profile including cholinesterase and BACE1 inhibition is described. Thus, the synthesis and evaluation of a new class of 5-substituted indazoles has been performed. Pharmacological evaluation includes in vitro inhibitory assays on AChE/BuChE and BACE1 enzymes. Also, the corresponding competition studies on BuChE were carried out. Additionally, antioxidant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory properties on Raw 264.7 cells and neuroprotective effects in human neuroblastoma SH-SY5Y cells have been performed. The results of pharmacological tests have shown that some of these 5-substituted indazole derivatives 1-4 and 6 behave as AChE/BuChE and BACE1 inhibitors, simultaneously. In addition, some indazole derivatives showed anti-inflammatory (3, 6) and neuroprotective (1-4 and 6) effects against Aß-induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.


Assuntos
Doença de Alzheimer , Neuroblastoma , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Aspártico Endopeptidases/metabolismo , Inibidores da Colinesterase , Humanos , Indazóis/farmacologia , Neuroblastoma/tratamento farmacológico , Relação Estrutura-Atividade
7.
Pharmaceuticals (Basel) ; 15(5)2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35631371

RESUMO

Multitarget anti-Alzheimer agents are the focus of very intensive research. Through a comprehensive bibliometric analysis of the publications in the period 1990-2020, we have identified trends and potential gaps that might guide future directions. We found that: (i) the number of publications boomed by 2011 and continued ascending in 2020; (ii) the linked-pharmacophore strategy was preferred over design approaches based on fusing or merging pharmacophores or privileged structures; (iii) a significant number of in vivo studies, mainly using the scopolamine-induced amnesia mouse model, have been performed, especially since 2017; (iv) China, Italy and Spain are the countries with the largest total number of publications on this topic, whereas Portugal, Spain and Italy are the countries in whose scientific communities this topic has generated greatest interest; (v) acetylcholinesterase, ß-amyloid aggregation, oxidative stress, butyrylcholinesterase, and biometal chelation and the binary combinations thereof have been the most commonly pursued, while combinations based on other key targets, such as tau aggregation, glycogen synthase kinase-3ß, NMDA receptors, and more than 70 other targets have been only marginally considered. These results might allow us to spot new design opportunities based on innovative target combinations to expand and diversify the repertoire of multitarget drug candidates and increase the likelihood of finding effective therapies for this devastating disease.

8.
Curr Top Med Chem ; 22(5): 333-346, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-34844540

RESUMO

Multifactorial diseases, such as cancer and diabetes present a challenge for the traditional "one-target, one disease" paradigm due to their complex pathogenic mechanisms. Although a combination of drugs can be used, a multitarget drug may be a better choice due to its efficacy, lower adverse effects and lower chance of resistance development. The computer-based design of these multitarget drugs can explore the same techniques used for single-target drug design, but the difficulties associated with the obtention of drugs that are capable of modulating two or more targets with similar efficacy impose new challenges, whose solutions involve the adaptation of known techniques and also to the development of new ones, including machine-learning approaches. In this review, some SBDD and LBDD techniques for the multitarget drug design are discussed, together with some cases where the application of such techniques led to effective multitarget ligands.


Assuntos
Desenho de Fármacos , Aprendizado de Máquina , Sistemas de Liberação de Medicamentos , Ligantes , Modelos Moleculares
9.
Eur J Pharmacol ; 914: 174686, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34883073

RESUMO

Alcoholic abuse is one of the most serious causes of liver diseases worldwide. Although detailed molecular pathogenesis of alcohol-induced liver damages remains elusive with intensive debates, it has been widely recognized that hepatic damage caused by free radicals generated from alcohol metabolism is one of the most critical factors for alcohol-induced liver diseases. Betulinic acid is a potent antioxidant with additional known pharmacological safety characteristics and minimal toxicity. However, poor solubility limited its usage. In this study, we assessed the efficacy of BAN, a betulinic acid and nucleoside hybrid with good water solubility, in reversing acute liver damages using an established alcohol overdose animal model. The results indicated that BAN is an extremely promising therapeutic agent against acute alcohol-induced liver damage. BAN effectively protects liver from alcohol damage by reducing serum ALT level by up to 47%, as well as liver oxidative stress indicated by significantly increased SOD, CAT, and GSH-Px levels. Moreover, hepatic FXR activation and a corresponding downstream anti-oxidative stress transcriptional cascade including Nrf2, HO-1, and NOQ1 induce the protective role of BAN. On the other hand, BAN administration also leads to increase cellular autophagy response, as indicated by the key ATG protein activation. We concluded that BAN, comparing with Betulinic acid, prevents acute alcohol-induced liver damages more effectively, with the dual mechanisms of neutralizing oxidative stress and promoting autophagy.


Assuntos
Etanol/metabolismo , Hepatopatias Alcoólicas , Fígado , Nucleosídeos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/terapia , Animais , Antioxidantes/farmacologia , Depressores do Sistema Nervoso Central/efeitos adversos , Depressores do Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Etanol/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Testes de Função Hepática , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Solubilidade , Ácido Betulínico
10.
J Biomol Struct Dyn ; 40(19): 8825-8839, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33931002

RESUMO

Cyclin-dependent kinases (CDKs) belong to a family of multifunctional enzymes that control cell cycle modifications, transcription, and cell proliferation. Their dysfunctions result in different diseases like cancer making them an important drug target in oncology and beyond. The present study aims at identifying the selective inhibitors for ATP binding site in CDK proteins (CDK1, CDK2, CDK4, and CDK5) following a multi-target drug designing approach. Significant challenges lie in identifying the selective inhibitor for the ATP binding site as this region is highly conserved in all protein kinases. Molecular docking coupled with molecular dynamics simulation and free energy of binding calculations (MMPBSA/MMGBSA) were used to identify the potent competitive ATP binding site inhibitors. All the four proteins were docked against the library of drug-like compounds and the outcomes of the docking study were further analyzed by Molecular dynamics (total of 6µs) and MMPB/GBSA techniques. Five different inhibitors for structurally distant protein kinases, i.e. CDK1, CDK2, CDK4, and CDK5 are identified with the binding energy (ΔGbind-PB) in the range -18.24 to -28.43Kcal/mol. Mechanistic complexities associated with the binding of the inhibitor are unraveled by carefully analyzing the MD trajectories. It is observed that certain residues (Lys33, Asp127, Asp145, Tyr15, Gly16, Asn144) and regions are critical for the retention of inhibitors in active pocket, and significant conformational changes take place in the active site region as well as its neighbor following the entry of the ligand inside active pocket as inferred by RMSD and RMSF. It is observed that LIG3 and LIG4 are the best possible inhibitors as reflected from their high binding energy, interaction pattern, and their retention inside the active pocket. This study will facilitate the process of multi-target drug designing against CDK proteins and can be used in the development of potential therapeutics against different diseases.


Assuntos
Proteínas de Ciclo Celular , Quinases Ciclina-Dependentes , Simulação de Acoplamento Molecular , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/metabolismo , Quinase 2 Dependente de Ciclina/química , Ciclo Celular , Trifosfato de Adenosina/metabolismo
11.
Curr Med Chem ; 29(28): 4796-4830, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34781863

RESUMO

Pharmacological treatment of complex pathologies, such as neurodegenerative diseases still represents a major challenge, due to the networked pathways involved in their onset and progression that may require equally complex therapeutic approaches. Polypharmacology, based on the simultaneous modulation of multiple targets involved in the disease, may offer the potential to increase effectiveness and reduce the drawbacks related to the use of drug combinations. Clearly, this approach requires both the knowledge of the systems responsible for disease development and the discovery of new attractive targets to be exploited to design a multitarget drug. Over the last years, an ever increasing interest has focused on the endocannabinoid system, implicated in the modulation of several physiological functions, among which neuroinflammation, a crucial process for most neurodegenerative diseases. In this respect, the cannabinoid receptor subtype 2 represents a promising therapeutic target, being overexpressed in microglia cells and thus involved in neuroinflammation. The indirect modulation of this system through the inhibition of the main enzymes responsible for endocannabinoids metabolism, namely fatty acid amide hydrolase and monoacylglycerol lipase, may also significantly affect neurodegenerative processes. The aim of this review is to give an overview of the opportunities posed by the endocannabinoid system for neurodegenerative diseases management, mainly focusing on the potential for a multitarget strategy.


Assuntos
Endocanabinoides , Doenças Neurodegenerativas , Amidoidrolases/metabolismo , Endocanabinoides/metabolismo , Humanos , Monoacilglicerol Lipases/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Polifarmacologia
12.
Pharmaceuticals (Basel) ; 14(9)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34577613

RESUMO

Metabolic syndrome (MetS) is a complex disease that affects almost a quarter of the world's adult population. In MetS, diabetes, obesity, hyperglycemia, high cholesterol, and high blood pressure are the most common disorders. Polypharmacy is the most used strategy for managing conditions related to MetS, but it has drawbacks such as low medication adherence. Multitarget ligands have been proposed as an interesting approach to developing drugs to treat complex diseases. However, suitable preclinical models that allow their evaluation in a context closer to a clinical situation of a complex disease are needed. From molecular docking studies, compound 1b, a 5-aminoanthranilic acid derivative substituted with 4'-trifluoromethylbenzylamino and 3',4'-dimethoxybenzamide moieties, was identified as a potential multitarget drug, as it showed high in silico affinity against targets related to MetS, including PPAR-α, PPAR-γ, and HMG-CoA reductase. It was evaluated in a diet-induced MetS rat model and simultaneously lowered blood pressure, glucose, total cholesterol, and triglyceride levels after a 14-day treatment. No toxicity events were observed during an acute lethal dose evaluation test at 1500 mg/kg. Hence, the diet-induced MetS model is suitable for evaluating treatments for MetS, and compound 1b is an attractive starting point for developing multitarget drugs.

13.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279369

RESUMO

In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.


Assuntos
Descoberta de Drogas/métodos , Neuralgia/tratamento farmacológico , Manejo da Dor/métodos , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canabinoides/química , Canabinoides/uso terapêutico , Humanos
14.
ACS Chem Neurosci ; 12(11): 2013-2026, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33977725

RESUMO

The triple reuptake inhibitors (TRIs) class is a class of effective inhibitors of human monoamine transporters (hMATs), which includes dopamine, norepinephrine, and serotonin transporters (hDATs, hNETs, and hSERTs). Due to the high degree of structural homology of the binding sites of those transporters, it is a great challenge to design potent TRIs with fine-tuned binding profiles. The molecular determinants responsible for the binding selectivity of TRIs to hDATs, hNETs, and hSERTs remain elusive. In this study, the solved X-ray crystallographic structure of hSERT in complex with escitalopram was used as a basis for modeling nine complexes of three representative TRIs (SEP225289, NS2359, and EB1020) bound to their corresponding targets. Molecular dynamics (MD) and effective post-trajectory analysis were performed to estimate the drug binding free energies and characterize the selective profiles of each TRI to hMATs. The common binding mode of studied TRIs to hMATs was revealed by hierarchical clustering analysis of the per-residue energy. Furthermore, the combined protein-ligand interaction fingerprint and residue energy contribution analysis indicated that several conserved and nonconserved "Warm Spots" such as S149, V328, and M427 in hDAT, F317, F323, and V325 in hNET and F335, F341, and V343 in hSERT were responsible for the TRI-binding selectivity. These findings provided important information for rational design of a single drug with better polypharmacological profiles through modulating multiple targets.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Sítios de Ligação , Citalopram , Humanos , Simulação de Dinâmica Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
15.
Curr Med Chem ; 28(12): 2305-2327, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32867634

RESUMO

The unmet need for the development of effective drugs to treat Alzheimer 's disease has been steadily growing, representing a major challenge in drug discovery. In this context, drug repurposing, namely the identification of novel therapeutic indications for approved or investigational compounds, can be seen as an attractive attempt to obtain new medications reducing both the time and the economic burden usually required for research and development programs. In the last years, several classes of drugs have evidenced promising beneficial effects in neurodegenerative diseases, and for some of them, preliminary clinical trials have been started. This review aims to illustrate some of the most recent examples of drugs reprofiled for Alzheimer's disease, considering not only the finding of new uses for existing drugs but also the new hypotheses on disease pathogenesis that could promote previously unconsidered therapeutic regimens. Moreover, some examples of structural modifications performed on existing drugs in order to obtain multifunctional compounds will also be described.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Humanos
16.
Med Res Rev ; 41(2): 803-827, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32687230

RESUMO

The mitochondria-targeting drugs can be conventionally divided into the following groups: those compensating for the energy deficit involved in neurodegeneration, including stimulants of mitochondrial bioenergetics and activators of mitochondrial biogenesis; and neuroprotectors, that are compounds increasing the resistance of mitochondria to opening of mitochondrial permeability transition (MPT) pores. Although compensating for the energy deficit and inhibition of MPT are obvious targets for drugs used in the very early stages of Alzheimer-like pathology, but their use as the monotherapy for patients with severe symptoms is unlikely to be sufficiently effective. It would be optimal to combine targets that would provide the cognitive-stimulating, the neuroprotective effects and the ability to affect specific disease-forming mechanisms. In the design of such drugs, assessment of their potential mitochondrial-targeted effects is of particular importance. The possibility of targeted drug design for simultaneous action on mitochondrial and neurotransmitter's receptors targets is, in particularly, based on the known interplay of various cellular pathways and the presence of common structural components. Of particular interest is directed search for multitarget drugs that would act simultaneously on mitochondrial calcium-dependent functions, the targets (receptors, enzymes, etc.) facilitating neurotransmission, and the molecular targets related to the action of so-called disease-modifying factors, in particular, the formation and overcoming of the toxicity of ß-amyloid or hyperphosphorylated tau protein. The examples of such approaches realized on the level of preclinical and clinical trials are presented below.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Humanos , Mitocôndrias , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
17.
Med Res Rev ; 41(5): 2606-2633, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32557696

RESUMO

The continued drug discovery failures in complex neurodegenerative diseases, including Alzheimer's disease (AD), has raised questions about the classical paradigm "one-drug, one-target, one-disease." In parallel, the ever-increasing awareness of the multiplicity of the underlying pathways has led to the affirmation of polypharmacological approaches. Polypharmacology, which broadly embodies the use of pharmaceutical agents acting on multiple targets, seems to be the best way to restore the complex diseased network and to provide disease-modifying effects in AD. In this review, our aim is to provide a roadmap into a world that is still only partly explored and that should be seen as a continuum of pharmacological opportunities, from drug combinations to multitarget-directed ligands (both codrugs and hybrids). Each modality has unique features that can be effectively exploited by medicinal chemists. We argue that understanding their advantages and drawbacks is very helpful in choosing a proper approach and developing successful AD multitarget drug-discovery endeavors. We also briefly dwell on (co)target validation, an aspect that is quite often neglected, but critical for an efficient clinical translation. We substantiate our discussion with instructive examples taken from the recent literature. Our wish is that, in spite of the specter of the high attrition rates, best researchers preferring to enter, stay, and progress in the field would help grow the sector and develop AD polypharmacology to full potential.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas , Humanos , Ligantes , Polifarmacologia
18.
Eur J Pharm Sci ; 156: 105594, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33059042

RESUMO

DNA Topoisomerases (Topos) are ubiquitous nuclear enzymes involved in regulating the topological state of DNA and, in eukaryotic organisms, Topos can be classified into two structurally and functionally different main classes: TopoI and TopoII. Both these enzymes proved to be excellent targets of clinically significant classes of anticancer drugs. Actually, TopoI or II inhibitors show considerable wide spectrum antitumor activities, an important feature to be included in many chemotherapeutic protocols. Despite their clinical efficacy, the use of inhibitors targeting only one of the two enzymes can increase the levels of the other one, favouring the onset of unwanted phenomena such as drug resistance. Therefore, targeting both TopoI and TopoII can reduce the probability of developing resistance, as well as side effects thanks to the use of lower doses, given the synergistic effect of the dual activity. Moreover, since drug resistance is also due to DNA repair systems such as tyrosyl-DNA phosphodiesterases I and II, inhibiting Topoisomerases concomitantly to Tyrosyl-DNA phosphodiesterase enzymes could allow more efficient and safe drugs. This review represents an update of previous works reporting about dual TopoI and TopoII inhibitors, but also an overview of the new strategy regarding the development of derivatives able to simultaneously inhibit Topo and TDP enzymes, with particular attention to structure-affinity relationship studies. The newly collected derivatives are described focusing attention on their chemical structures and their biological profiles. The final aim is to highlight the structural requirements necessary for the development of potent multiple modulators of these targets, thus providing new potential antitumor agents for the clinical usage.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo I , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA , Diester Fosfórico Hidrolases , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia
19.
Bioorg Med Chem Lett ; 30(18): 127424, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738747

RESUMO

Chemoresistance is thought to be the cause of low treatment efficacy and mortality in more than 90% of patients with advanced cancer. The activation of drug efflux by P-glycoprotein is the key mechanism of resistance. All known P-gp inhibitors are used only in the combination therapy. We propose a new approach based on the multitarget rational design of drugs, which possess both the antitumor and efflux pump inhibitory activity. In this work, the principle possibility of combining the ability to inhibit P-gp and p53-Mdm2 protein-protein interaction in one structure is considered. The biological activity of a number of known and newly synthesized compounds was evaluated using cell lines with different p53 status. The possibility of using computer modeling for the search for P-glycoprotein inhibitors among Mdm2 inhibitors was analyzed; P-gp interaction site and binding modes of substrates and inhibitors were identified. The results obtained in cells that have the native balance of drug resistance and sensitivity showed the ability of the cells to both actively throw out xenobiotics and to lose this ability using P-gp inhibitors. The data obtained indicate that Mdm2 inhibitors are a promising platform for the development of multitarget drugs that can overcome tumor resistance by inhibiting the P-glycoprotein activity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/química , Inibidores Enzimáticos/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Antineoplásicos/farmacologia , Simulação por Computador , Resistência a Múltiplos Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Imidazóis/química , Isatina/química , Modelos Moleculares , Piperazinas/química , Ligação Proteica , Quinolinas/química , Relação Estrutura-Atividade
20.
Molecules ; 25(15)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32717806

RESUMO

Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3ß), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores Enzimáticos/farmacologia , Acetilcolinesterase , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Proteínas Ligadas por GPI/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Ligantes , Estrutura Molecular , Monoaminoxidase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Polifarmacologia , Receptores Histamínicos H3/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de Serotonina/metabolismo
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