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1.
Chem Pharm Bull (Tokyo) ; 68(1): 34-45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902900

RESUMO

Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.


Assuntos
Carboxiliases/metabolismo , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Lisina/química , Carboxiliases/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Histona Desmetilases/antagonistas & inibidores , Humanos , Lisina/metabolismo , Processamento de Proteína Pós-Traducional , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Enzimas de Conjugação de Ubiquitina/metabolismo
2.
J Enzyme Inhib Med Chem ; 35(1): 289-297, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797703

RESUMO

In this study, newly synthesised compounds 6, 8, 10 and other compounds (1-5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1-10 showed effective inhibition profiles with KI values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Desenho de Drogas , Pirazóis/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
3.
J Enzyme Inhib Med Chem ; 35(1): 72-84, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682465

RESUMO

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Desenho de Drogas , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
4.
J Enzyme Inhib Med Chem ; 35(1): 152-164, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31742469

RESUMO

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Terpenos/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química
5.
Zhongguo Zhong Yao Za Zhi ; 44(22): 4874-4879, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872595

RESUMO

According to drug design flattening principle and using podophyllotoxin or 4'-demethylepipodophyllotoxin and aldehydes as starting material,a series of podophyllotoxin derivatives containing an imine structure with low toxicity were highly effective synthesized. Nine target compounds were successfully synthesized,and their structures were confirmed by ~1H-NMR,HR-ESI-MS and melting point data analysis. Using etoposide as positive control drug,nine target compounds were screened for cytotoxicity against He La cells in vitro by MTT method. The antitumor activity screening results showed that compound 6 b,6 d,6 e,6 f,6 g,6 i exhibited higher inhibitory rate against He La cells than those of control drug VP-16. It provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Podofilotoxina/farmacologia , Desenho de Drogas , Relação Estrutura-Atividade
6.
Chimia (Aarau) ; 73(12): 1006-1011, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31883552

RESUMO

Drug discovery benefits from computational models aiding the identification of new chemical matter with bespoke properties. The field of de novo drug design has been particularly revitalized by adaptation of generative machine learning models from the field of natural language processing. These deep neural network models are trained on recognizing molecular structures and generate new molecular entities without relying on pre-determined sets of molecular building blocks and chemical transformations for virtual molecule construction. Implicit representation of chemical knowledge provides an alternative to formulating the molecular design task in terms of the established, explicit chemical vocabulary. Here, we review de novo molecular design approaches from the field of 'artificial intelligence', focusing on instances of deep generative models, and highlight the prospective application of long short-term memory models to hit and lead finding in medicinal chemistry.


Assuntos
Memória de Curto Prazo , Desenho de Drogas , Aprendizado de Máquina , Estudos Prospectivos
7.
Phys Chem Chem Phys ; 21(44): 24269-24285, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31670327

RESUMO

An enormous population worldwide is presently confronted with debilitating neurodegenerative diseases. The etiology of the disease is connected to protein aggregation and the events involved therein. Thus, a complete understanding of an inhibitor at different stages in the process is imperative for the formulation of a drug molecule. This review presents a detailed summary of the current status of different cosolvents. It further develops how the complex aggregation pathway can be simplified into three steps common to all proteins and the way computer simulations can be exploited to gain insights into the ways by which known inhibitors can affect all these stages. Computation of theoretical parameters in this regard and their correlation with experimental techniques is accentuated. In addition to providing an outline of the scope of different additives, this review showcases the way by which the problem of analyzing an effect of an additive can be addressed effectively via MD simulations.


Assuntos
Proteínas/química , Antioxidantes/química , Antioxidantes/farmacologia , Desenho de Drogas , Humanos , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/farmacologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Agregados Proteicos/efeitos dos fármacos , Proteínas/metabolismo
8.
Adv Exp Med Biol ; 1163: 1-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707697

RESUMO

Allosteric regulation is a ubiquitous strategy employed in nature to control cellular processes by regulating the affinities of biomolecules. Allosteric modulators are able to tune the protein/substrate affinity in a highly predictable way, suggesting that such modulators may represent safe drugs. Tremendous advances have been made in the development of allosteric modulators and the characterization of their therapeutic targets. Here, we briefly introduce several representative allosteric modulators of important drug targets, such as the G protein-coupled receptor family. We also review the state-of-the-art experimental and computational approaches used in allosteric drug development. The accumulated knowledge of allosteric regulation and the technical progress made in drug development will lead to an explosion of promising allosteric drugs in the near future.


Assuntos
Desenvolvimento de Medicamentos , Regulação Alostérica , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Desenvolvimento de Medicamentos/tendências , Humanos
9.
Adv Exp Med Biol ; 1163: 45-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707699

RESUMO

This chapter focuses on protein kinases that transfer the phosphate group of ATP to the hydroxyl group of a substrate protein. Five hundred eighteen human protein kinases are classified into serine/threonine kinases and tyrosine kinases and individually or synergistically transduce physiologic stimuli into cell to promote cell proliferation or apoptosis, etc. Protein kinases are identified as drug targets because dysfunction of kinases leads to severe diseases such as cancers and autoimmune diseases. A large number of the crystal structures of the protein kinase inhibitor complex are available in Protein Data Bank and facilitated the drug discovery targeting protein kinases. The protein kinase inhibitors are classified into categories, Type-I, Type-II, Type-III, Type-IV, and Type-V, and as a separate class, covalent-type inhibitors. In any type, a protein kinase inhibitor bound to the allosteric region is advantageous in terms of selectivity compared to the traditional ATP-competitive one. In the following sections, the successful and promising examples of the partially or fully allosteric protein kinase inhibitors are illustrated in the following pages.


Assuntos
Desenho de Drogas , Inibidores de Proteínas Quinases , Proteínas Quinases , Trifosfato de Adenosina , Descoberta de Drogas , Ativação Enzimática/efeitos dos fármacos , Humanos , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo
10.
Prog Chem Org Nat Prod ; 110: 99-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621012

RESUMO

Pharmacophore-based techniques currently are an integral part of many computer-aided drug design workflows and have been successfully and extensively applied for tasks such as virtual screening, de novo design, and lead optimization. Pharmacophore models can be derived both in a receptor-based and in a ligand-based manner, and provide an abstract description of essential non-bonded interactions that typically occur between small-molecule ligands and macromolecular targets. Due to their simplistic and abstract nature, pharmacophores are both perfectly suited for efficient computer processing and easy to comprehend by life and physical scientists. As a consequence, they have also proven to be a valuable tool for communicating between computational and medicinal chemists.This chapter aims to provide a short overview of the pharmacophore concept and its applications in modern computer-aided drug design. The chapter is divided into three distinct parts. The first section contains a brief introduction to the pharmacophore concept. The second section provides a description of the most common nonbonded interaction types and their representation as pharmacophoric features. Furthermore, it gives an overview of the various methods for pharmacophore generation and important pharmacophore-based techniques in drug design. This part concludes with examples for recent pharmacophore concept-related research and development. The last section is dedicated to a review of research in the field of natural product chemistry as carried out by employing pharmacophore-based drug design methods.


Assuntos
Química Farmacêutica , Projeto Auxiliado por Computador , Desenho de Drogas , Produtos Biológicos/química , Ligantes , Receptores de Droga
12.
Expert Opin Investig Drugs ; 28(11): 1013-1020, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31596151

RESUMO

Introduction: Corneal ulcers normally resolve spontaneously because of the proliferative ability of the corneal epithelium; however, sometimes, epithelial healing is diminished, even when standard treatments are administered. Hence, the treatment of refractory corneal ulcers is challenging and is the subject of ongoing efforts in preclinical and clinical development. Emerging treatment approaches include thymosine ß4, CODA001, and topical insulin. Cenegermin eye drops, containing recombinant human nerve growth factor and ReGenerating Agent, a matrix therapy agent, have recently been commercialized for the treatment of moderate to severe neurotrophic keratitis in adults.Areas covered: We describe emerging therapeutic approaches for the management of refractory corneal ulcers and treatments recently introduced to the market. Pubmed and Clinicaltrial.gov databases were first searched including the terms: "corneal ulcer" or "neurotrophic keratopathy" and "treatment." Each treatment was searched in the same databases separately.Expert opinion: Affections of the sensory corneal nerves are the main factor contributing to the pathophysiology of neurotrophic keratopathy; this explains the healing difficulties of this form of ulcer. Cenegermin is a promising therapy acting as a neurotrophic agent for corneal healing. ReGenerating Agent has led to rapid pain relief and corneal healing, but randomized clinical trials are still necessary for further assessment.


Assuntos
Úlcera da Córnea/tratamento farmacológico , Desenho de Drogas , Ceratite/tratamento farmacológico , Adulto , Animais , Úlcera da Córnea/patologia , Epitélio Anterior/efeitos dos fármacos , Epitélio Anterior/patologia , Humanos , Ceratite/patologia , Fator de Crescimento Neural/administração & dosagem
13.
Chem Commun (Camb) ; 55(85): 12845-12848, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31596280

RESUMO

Multivalent mannosides with inherent macrophage recognition abilities, built on ß-cyclodextrin, RAFT cyclopeptide or peptide dendrimer cores, trigger selective inhibition of lysosomal ß-glucocerebrosidase or α-mannosidase depending on valency and topology, offering new opportunities in multitargeted drug design.


Assuntos
Desenho de Drogas , Manosídeos/química , Glucosilceramidase/antagonistas & inibidores , Lectinas/química , Macrófagos/metabolismo , Manosídeos/metabolismo , Peptídeos Cíclicos/química , alfa-Manosidase/antagonistas & inibidores , beta-Ciclodextrinas/química
14.
Expert Opin Ther Pat ; 29(10): 781-792, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31596641

RESUMO

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called 'old drugs' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.


Assuntos
Inibidores da Anidrase Carbônica/administração & dosagem , Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Animais , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Desenho de Drogas , Reposicionamento de Medicamentos , Glaucoma/enzimologia , Humanos , Hipertensão Ocular/enzimologia , Patentes como Assunto
15.
Chem Pharm Bull (Tokyo) ; 67(10): 1116-1122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582631

RESUMO

In recent studies, combinations of histone deacetylases (HDACs) inhibitor with kinase inhibitor showed additive and synergistic effects. BRafV600E as an attractive target in many diseases treatments has been studied extensively. Herein, we present a novel design approach though incorporating the pharmacophores of BRafV600E inhibitor and HDACs inhibitor in one molecule. Several synthesized compounds exhibited distinct BRafV600E and HDAC1 inhibitory activities. The representative dual Raf/HDAC inhibitor, 7a, showed better antiproliferative activities against A549 and SK-Mel-2 in cellular assay than SAHA and sorafenib, with IC50 values of 9.11 µM and 5.40 µM, respectively. This work may lay the foundation for the further development of dual Raf/HDAC inhibitors as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
Chem Pharm Bull (Tokyo) ; 67(10): 1144-1151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582634

RESUMO

Definitive screening design (DSD) is a new class of small three-level experimental design that is attracting much attention as a technical tool of a quality by design (QbD) approach. The purpose of this study is to examine the usefulness of DSD for QbD through a pharmaceutical study on the preparation of ethenzamide-containing orally disintegrating tablet. Model tablets were prepared by directly compressing the mixture of the active pharmaceutical ingredient (API) and excipients. The five evaluated factors assigned to DSD were: the contents of API (X1) and lubricant (X2), and the compression force (X3) of the tableting process, the mixing time (X4), and the filling ratio of powder in the V-type mixer (X5). After tablet preparation, hardness and disintegration time were measured. The same experiments were performed by using the conventional design of experiments [i.e., L8 and L16 orthogonal array designs and central composite design (CCD)]. Results showed that DSD successfully clarified how various factors contribute to tablet properties. Moreover, the analysis result from DSD agreed well with those from the L8 and L16 experiments. In additional experiments, response surfaces for tablet properties were created by DSD. Compared with the response surfaces created by CCD, DSD could produce reliable response surfaces for its smaller number of experiments. We conclude that DSD is a powerful tool for implementing pharmaceutical studies including the QbD approach.


Assuntos
Desenho de Drogas , Preparações Farmacêuticas/química , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Propriedades de Superfície , Comprimidos/administração & dosagem , Comprimidos/química
18.
Expert Rev Clin Pharmacol ; 12(11): 1037-1046, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607179

RESUMO

Introduction: Antimicrobial resistance poses a substantial threat to global public health since it decreases the probability of effectively treating an infection and increases the risk of morbidity and mortality.Areas covered: In this review, the authors discuss the advantages and disadvantages of classical and novel trial designs for evaluating novel antibiotics for infections due to multidrug-resistant organisms (MDRO). An inductive literature search was performed using different keywords pertinent to the reviewed topics.Expert opinion: The need for active, effective compounds has strengthened regulatory, academic, and industry cooperation, leading to the recent approval of some novel anti-MDRO agents, with other promising compounds being also in the late phase of clinical development. Nonetheless, some important issues regarding the design of clinical trials have gained importance that are peculiar for novel anti-MDRO agents and should be addressed for continuing to guarantee the availability of effective treatments in the future. Very importantly, concerted cooperation with regulatory agencies will always be needed for continuously discussing and refining the acceptable level of evidence to be pursued through non-conventional and/or innovative trial designs or development strategies. Failure to do so would seriously pose the risk of perpetuating the unmet need for effective anti-MDRO agents.


Assuntos
Antibacterianos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Projetos de Pesquisa , Adulto , Antibacterianos/farmacologia , Desenho de Drogas , Farmacorresistência Bacteriana Múltipla , Humanos
19.
J Chem Theory Comput ; 15(11): 6243-6253, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589430

RESUMO

In this study, we present a fully automatic platform based on our Monte Carlo algorithm, the Protein Energy Landscape Exploration method (PELE), for the estimation of absolute protein-ligand binding free energies, one of the most significant challenges in computer aided drug design. Based on a ligand pathway approach, an initial short enhanced sampling simulation is performed to identify reasonable starting positions for more extended sampling. This stepwise approach allows for a significant faster convergence of the free energy estimation using the Markov State Model (MSM) technique. PELE-MSM was applied on four diverse protein and ligand systems, successfully ranking compounds for two systems. Based on the results, current limitations and challenges with physics-based methods in computational structural biology are discussed. Overall, PELE-MSM constitutes a promising step toward computing absolute binding free energies and in their application into drug discovery projects.


Assuntos
Algoritmos , Proteínas/química , Desenho de Drogas , Ligantes , Cadeias de Markov , Método de Monte Carlo , Ligação Proteica , Proteínas/metabolismo , Termodinâmica
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