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1.
Methods Mol Biol ; 2114: 307-337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32016901

RESUMO

Quantum mechanics/molecular mechanics (QM/MM) hybrid technique is emerging as a reliable computational method to investigate and characterize chemical reactions occurring in enzymes. From a drug discovery perspective, a thorough understanding of enzyme catalysis appears pivotal to assist the design of inhibitors able to covalently bind one of the residues belonging to the enzyme catalytic machinery. Thanks to the current advances in computer power, and the availability of more efficient algorithms for QM-based simulations, the use of QM/MM methodology is becoming a viable option in the field of covalent inhibitor design. In the present review, we summarized our experience in the field of QM/MM simulations applied to drug design problems which involved the optimization of agents working on two well-known drug targets, namely fatty acid amide hydrolase (FAAH) and epidermal growth factor receptor (EGFR). In this context, QM/MM simulations gave valuable information in terms of geometry (i.e., of transition states and metastable intermediates) and reaction energetics that allowed to correctly predict inhibitor binding orientation and substituent effect on enzyme inhibition. What is more, enzyme reaction modelling with QM/MM provided insights that were translated into the synthesis of new covalent inhibitor featured by a unique combination of intrinsic reactivity, on-target activity, and selectivity.


Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/química , Amidoidrolases/química , Catálise , Desenho de Fármacos , Receptores ErbB/química , Simulação de Dinâmica Molecular , Teoria Quântica
2.
Eur J Med Chem ; 189: 112083, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32000051

RESUMO

The EphA2 receptor has been validated in animal models as new target for treating tumors depending on angiogenesis and vasculogenic mimicry. In the present work, we extended our current knowledge on structure-activity relationship (SAR) data of two related classes of antagonists of the EphA2 receptor, namely 5ß-cholan-24-oic acids and 5ß-cholan-24-oyl l-ß-homotryptophan conjugates, with the aim to develop new antiangiogenic compounds able to efficiently prevent the formation of blood vessels. As a result of our exploration, we identified UniPR505, N-[3α-(Ethylcarbamoyl)oxy-5ß-cholan-24-oyl]-l-ß-homo-tryptophan (compound 14), as a submicromolar antagonist of the EphA2 receptor capable to block EphA2 phosphorylation and to inhibit neovascularization in a chorioallantoic membrane (CAM) assay.


Assuntos
Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/normas , Ácido Litocólico/química , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor EphA2/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Proliferação de Células , Embrião de Galinha , Galinhas , Membrana Corioalantoide , Humanos , Masculino , Modelos Moleculares , Fosforilação , Compostos Policíclicos/química , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/normas , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Eur J Med Chem ; 162: 507-524, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472599

RESUMO

Second- and third-generation inhibitors of EGFR possess an acrylamide group which alkylates Cys797, allowing to overcome resistance due to insurgence of T790M mutation. Less reactive warheads, yet capable to bind the target cysteine, may be useful to design newer and safer inhibitors. In the present work, we synthesized a 2-chloro-N-(4-(phenylamino)quinazolin-6-yl)acetamide (8) derivative as a prototype of EGFR inhibitor potentially able to react with Cys797 by nucleophilic substitution. We then tuned the reactivity of the acetamide fragment by replacing the chlorine leaving group with (hetero)-aromatic thiols or carboxylate esters. Among the synthesized derivatives, the 2-((1H-imidazol-2-yl)thio)acetamide 16, while showing negligible reactivity with cysteine in solution, caused long-lasting inhibition of wild-type EGFR autophosphorylation in A549 cells, resulted able to bind recombinant EGFR L858R/T790M in a time-dependent manner, and inhibited both EGFR autophosphorylation and proliferation in gefitinib-resistant H1975 lung cancer cells (expressing EGFR L858R/T790M mutant) at low micromolar concentration.


Assuntos
Antineoplásicos/farmacologia , Tioacetamida/farmacologia , Células A549 , Acetamidas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisteína/metabolismo , Receptores ErbB/antagonistas & inibidores , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação , Tioacetamida/análogos & derivados , Tioacetamida/síntese química
4.
Biochem Pharmacol ; 147: 21-29, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29129483

RESUMO

Eph/ephrin system is an emerging target for cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129. These two compounds acted as competitive and reversible antagonists of all Eph receptors reducing both ephrin-A1 and -B1 binding to EphAs and EphBs receptors in the low micromolar range. The compounds acted as antagonists inhibiting ephrin-A1-dependent EphA2 activation and UniPR139 exerted an anti-angiogenic effect, inhibiting HUVEC tube formation in vitro and VEGF-induced vessel formation in the chick chorioallantoic membrane assay. Finally, the oral bioavailability of UniPR139 represents a step forward in the search of molecules targeting the Eph/ephrin system and offers a new pharmacological tool useful for future in vivo studies.


Assuntos
Sistemas de Liberação de Medicamentos , Efrinas/metabolismo , Ácido Litocólico/análogos & derivados , Triptofano/análogos & derivados , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Embrião de Galinha , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Ácido Litocólico/química , Ácido Litocólico/metabolismo , Ligação Proteica/fisiologia , Triptofano/química , Triptofano/metabolismo
6.
J Chem Inf Model ; 57(2): 159-169, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28080056

RESUMO

The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times.


Assuntos
Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinase 8 Dependente de Ciclina/química , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Termodinâmica , Fatores de Tempo
7.
J Med Chem ; 60(2): 787-796, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28005388

RESUMO

Metadynamics (META-D) is emerging as a powerful method for the computation of the multidimensional free-energy surface (FES) describing the protein-ligand binding process. Herein, the FES of unbinding of the antagonist N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan (UniPR129) from its EphA2 receptor was reconstructed by META-D simulations. The characterization of the free-energy minima identified on this FES proposes a binding mode fully consistent with previously reported and new structure-activity relationship data. To validate this binding mode, new N-(3α-hydroxy-5ß-cholan-24-oyl)-l-ß-homotryptophan derivatives were designed, synthesized, and tested for their ability to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists, namely compounds 21 and 22, displayed high affinity versus the EphA2 receptor and resulted endowed with better physicochemical and pharmacokinetic properties than the parent compound. These findings highlight the importance of free-energy calculations in drug design, confirming that META-D simulations can be used to successfully design novel bioactive compounds.


Assuntos
Simulação por Computador , Desenho de Fármacos , Ácido Litocólico/análogos & derivados , Receptor EphA2/antagonistas & inibidores , Triptofano/análogos & derivados , Animais , Estabilidade de Medicamentos , Ligantes , Ácido Litocólico/administração & dosagem , Ácido Litocólico/síntese química , Ácido Litocólico/química , Ácido Litocólico/farmacocinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor EphA2/química , Relação Estrutura-Atividade , Triptofano/administração & dosagem , Triptofano/síntese química , Triptofano/química , Triptofano/farmacocinética
8.
Chemistry ; 22(24): 8048-52, 2016 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-27139720

RESUMO

The free-energy surface (FES) of protein-ligand binding contains information useful for drug design. Here we show how to exploit a free-energy minimum of a protein-ligand complex identified by metadynamics simulations to design a new EphA2 antagonist with improved inhibitory potency.


Assuntos
Desenho de Fármacos , Receptor EphA2/metabolismo , Sítios de Ligação , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptor EphA2/antagonistas & inibidores , Ressonância de Plasmônio de Superfície , Termodinâmica
9.
Eur J Med Chem ; 103: 312-24, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26363867

RESUMO

The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic therapies. Research programs aimed at developing small-molecule antagonists of the Eph receptors are still in their initial stage as available compounds suffer from pharmacological drawbacks, limiting their application in vitro and in vivo. In the present work, we report the design, synthesis and evaluation of structure-activity relationships of a class of Δ(5)-cholenoyl-amino acid conjugates as Eph-ephrin antagonists. As a major achievement of our exploration, we identified N-(3ß-hydroxy-Δ(5)-cholen-24-oyl)-L-tryptophan (UniPR1331) as the first small molecule antagonist of the Eph-ephrin system effective as an anti-angiogenic agent in endothelial cells, bioavailable in mice by the oral route and devoid of biological activity on G protein-coupled and nuclear receptors targeted by bile acid derivatives.


Assuntos
Aminoácidos/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Efrinas/antagonistas & inibidores , Receptores da Família Eph/antagonistas & inibidores , Aminoácidos/síntese química , Aminoácidos/química , Inibidores da Angiogênese/síntese química , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Efrinas/química , Humanos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Receptores da Família Eph/química , Relação Estrutura-Atividade
10.
Molecules ; 20(9): 17132-51, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26393553

RESUMO

The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 receptor. However, these compounds suffer from poor physicochemical properties, hampering their use in vivo. The identification of compounds able to disrupt the EphA2-ephrin-A1 complex lacking the bile acid scaffold may lead to new pharmacological tools suitable for in vivo studies. To identify the most promising virtual screening (VS) protocol aimed at finding novel EphA2 antagonists, we investigated the ability of both ligand-based and structure-based approaches to retrieve known EphA2 antagonists from libraries of decoys with similar molecular properties. While ligand-based VSs were conducted using UniPR129 and ephrin-A1 ligand as reference structures, structure-based VSs were performed with Glide, using the X-ray structure of the EphA2 receptor/ephrin-A1 complex. A comparison of enrichment factors showed that ligand-based approaches outperformed the structure-based ones, suggesting ligand-based methods using the G-H loop of ephrin-A1 ligand as template as the most promising protocols to search for novel EphA2 antagonists.


Assuntos
Descoberta de Drogas/métodos , Efrina-A1/agonistas , Inibidores de Proteínas Quinases/química , Receptor EphA2/antagonistas & inibidores , Cristalografia por Raios X , Bases de Dados de Produtos Farmacêuticos , Efrina-A1/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Interface Usuário-Computador
11.
Mol Nutr Food Res ; 59(11): 2155-67, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26307544

RESUMO

SCOPE: The Eph-ephrin system comprises emerging proteins involved in many pathophysiological processes. The pharmacological activity of the main metabolites derived from the intake of some classes of (poly)phenolic compounds, such as caffeoylquinic acids, flavan-3-ols, and ellagitannins, on the Eph-ephrin interaction was evaluated at physiological concentrations. Functional studies to elucidate their role in prostate cancer were also performed. METHODS AND RESULTS: Among the 21 phenolics screened by an ELISA-binding assay, just urolithin C, urolithin D, and ellagic acid succeeded to inhibit the EphA2-ephrin-A1 binding. Urolithin D, the most active, was a competitive and reversible antagonist of EphA receptors able to discriminate between EphA and EphB receptors, showing intra-classes selectivity. Molecular modeling and structure-activity relationships shed light on the binding mode and selective activity of urolithin D. This catabolite blocked EphA2 phosphorylation mediated by ephrin-A1, while lacking cytotoxicity and anti-proliferative effects, and was inactive on the EphA2 kinase assay. CONCLUSION: The mechanisms behind the cancer preventive properties of foods rich in flavan-3-ols and caffeoylquinic acids are not associated with metabolic pathways directly linked to the Eph-ephrin system. However, the ellagitannin-derived colonic metabolite urolithin D was able to exert remarkable and selective EphA-ephrin-A inhibition, which might impact on prostate cancer prevention.


Assuntos
Anticarcinógenos/farmacologia , Cumarínicos/farmacologia , Neoplasias da Próstata/patologia , Receptor EphA2/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Taninos Hidrolisáveis/metabolismo , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Fosforilação , Receptor EphA2/química , Receptor EphA2/metabolismo
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