RESUMEN
Neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.
Asunto(s)
Diseño de Fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Humanos , Enfermedad de Huntington , Simulación del Acoplamiento Molecular/métodos , Simulación del Acoplamiento Molecular/tendencias , Enfermedad de ParkinsonRESUMEN
Resveratrol is a polyphenolic antioxidant derived from plant products such as grapes. Previous studies explored the effects of resveratrol on pulmonary hypertension (PH). However, systematic research on the exact mechanism of action of resveratrol is still lacking; in particular, our knowledge on the molecule-gene interaction is limited. In this study, systematic pharmacology and bioinformatic approaches were employed to identify the potential targets of resveratrol for treating PH. Furthermore, core genes were identified by constructing a protein-protein interaction network and by conducting topology analyses. The results showed that the effect of resveratrol may be closely associated with targets such as AKT serine/threonine kinase 1 (AKT1), mitogen-activated protein kinase 3 (MAPK3), Sirtuin-1 (SIRT1) and proto-oncogene tyrosine-protein kinase Src (SRC), as well as biological processes such as cell proliferation, inflammatory response, and redox balance. The present study systematically elucidates the mechanisms by which resveratrol alleviates PH and provides a new perspective on drug research for this disease.
Asunto(s)
Antioxidantes/uso terapéutico , Redes Reguladoras de Genes/genética , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/genética , Resveratrol/uso terapéutico , Tecnología Farmacéutica/métodos , Antioxidantes/metabolismo , Antioxidantes/farmacología , Minería de Datos/métodos , Minería de Datos/tendencias , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Hipertensión Pulmonar/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Simulación del Acoplamiento Molecular/métodos , Simulación del Acoplamiento Molecular/tendencias , Proto-Oncogenes Mas , Resveratrol/metabolismo , Resveratrol/farmacología , Sirtuina 1/genética , Sirtuina 1/metabolismo , Tecnología Farmacéutica/tendenciasRESUMEN
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Asunto(s)
Antineoplásicos/química , Descubrimiento de Drogas/métodos , Mutación/genética , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Animales , Antineoplásicos/farmacología , Diseño de Fármacos , Descubrimiento de Drogas/tendencias , Humanos , Simulación del Acoplamiento Molecular/métodos , Simulación del Acoplamiento Molecular/tendencias , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Drug repurposing is an unconventional drug discovery approach to explore new therapeutic benefits of existing, shelved and the drugs in clinical trials. This approach is currently emerging to overcome the bottleneck constraints faced during traditional drug discovery in grounds of financial support, timeline and resources. In this direction, several efforts were made for the construction of stratagems based on bioinformatics and computational tools to intensify the repurposing process off-late. Further, advanced research has succeeded in widening its boundaries in identification of gene targets and subsequent molecular interactions of the drugs depending on available omics data. Currently, the advent of data repositories like Connectivity Map (CMap), Library Integrated Network based Cellular Signatures (LINCS), Genome Wide Association Studies (GWAS), Side Effect Resource (SIDER), and Directionality Map (DMAP) has bestowed great oppurtunity to the researchers in improving their drug repurposing research exponentially. On the otherhand, in silico approaches like pharmacophore modelling and docking techniques circumvent the routine tedious in vitro and in vivo techniques involved in former screening phases of the drugs and disease specific targets. This review elaborates on currently designed contemporary tools, databases and strategies with relevant case studies.
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Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos/métodos , Simulación del Acoplamiento Molecular/métodos , Animales , Bases de Datos Factuales/tendencias , Descubrimiento de Drogas/tendencias , Reposicionamiento de Medicamentos/tendencias , Estudio de Asociación del Genoma Completo/métodos , Estudio de Asociación del Genoma Completo/tendencias , Humanos , Simulación del Acoplamiento Molecular/tendenciasRESUMEN
BACKGROUND: Glycogen synthase kinase-3ß plays a significant role in the regulation of various pathological pathways relating to the Central Nervous System (CNS). Dysregulation of Glycogen synthase kinase 3 (GSK-3) activity gives rise to numerous neuroinflammation and neurodegenerative related disorders that affect the whole central nervous system. OBJECTIVE: By the sequential application of in-silico tools, efforts have been attempted to design the novel GSK-3ß inhibitors. METHOD: Owing to the potential role of GSK-3ß in nervous disorders, we have attempted to develop the quantitative four featured pharmacophore model comprising two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), which were further affirmed by costfunction analysis, rm2 matrices, internal and external test set validation and Guner-Henry (GH) scoring analysis. Validated pharmacophoric model was used for virtual screening and out of 345 compounds, two potential virtual hits were finalized that were on the basis of fit value, estimated activity and Lipinski's violation. The chosen compounds were subjected to dock within the active site of GSK-3ß. RESULT: Four essential features, i.e., two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), were subjected to build the pharmacophoric model and showed good correlation coefficient, RMSD and cost difference values of 0.91, 0.94 and 42.9 respectively and further model was validated employing cost-function analysis, rm2-matrices, internal and external test set prediction with r2 value of 0.77 and 0.84. Docked conformations showed potential interactions in between the features of the identified hits (NCI 4296, NCI 3034) and the amino acids present in the active site. CONCLUSION: In line with the overhead discussion, and through our stepwise computational approaches, we have identified novel, structurally diverse glycogen synthase kinase inhibitors.
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Simulación por Computador , Minería de Datos/métodos , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Simulación del Acoplamiento Molecular/métodos , Pirimidinas/química , Minería de Datos/tendencias , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Ligandos , Simulación del Acoplamiento Molecular/tendencias , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Mature T-cell lymphomas are a heterogeneous group of T-cell malignancies with a poor outcome. The discovery of new molecular biomarkers has led to the emergence of new drugs in recent years that target various signaling pathways. METHODS: We examined all pertinent published patents through 2015 that analyzed novel methods for the diagnosis and treatment of T cell lymphoma, as well as related published and unpublished studies. Selection criteria were established before data collection. An exhaustive literature search was performed using MEDLINE and Science Direct databases. The search criteria were T-cell lymphoma, diagnosis, and treatment. RESULTS: Recent papers have identified recurrent epigenetic factor mutations in RHOA and FYN kinase in PTCL allowing new perspectives for epigenetic-based therapy, molecular classification model using CD28, ABCA5 transporter, coiled-coil domain-containing protein 3, and angiogenic factor SMOC2 biomarkers for differentiating forms of lymphomas, as well as expression of receptors forTNFR-1, TNFR-2, and IL12p40/70 in CTCL. New therapeutic targets have been reported such as MicroRNAs - 155 inhibitors and synthetic Toll-Like Receptor 7/8 agonists for treating CTCL, Anti CTLA-4 antibodies, anti- Killer cell immunoglobulin-like receptors 3DL2 and NK-p46 (NCR receptors) antibodies for treating PTCL, Cd1d antagonist-restricted gamma/delta-T cell lymphomas, antiEZH2, novel antihistone deacetylase, and NK cells engineered therapy. In the transplantation setting, the objective was to eradicate overcoming of the residual disease immunity and to induce an immune tolerance by anti-third part cells with a central memory T-lymphocyte phenotype. CONCLUSION: Therapeutic strategies based on a better molecular characterization of various histological types are certain to be used in the future.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Epigénesis Genética/efectos de los fármacos , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/metabolismo , Patentes como Asunto , Animales , Antineoplásicos/química , Epigénesis Genética/fisiología , Humanos , Linfoma de Células T/genética , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Simulación del Acoplamiento Molecular/métodos , Simulación del Acoplamiento Molecular/tendencias , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
Voltage-gated ion channels (VGICs) are responsible for the propagation of electrical signals in excitable cells. Small-molecule modulation of VGICs affects transmission of action potentials in neurons and thus can modulate the activity of the central nervous system. For this reason, VGICs are considered key players in the medically induced state of general anesthesia. Consistently, VGICs have been shown to respond to several general anesthetics. However, in spite of extensive electrophysiological characterizations, modulation of VGICs by anesthetics is still only partially understood. Among the challenging aspects are the presence of multiple binding sites and the observation of paradoxical effects, i.e., evidence, for the same channel, of inhibition and potentiation. In this context, molecular simulations emerged in the recent past as the tool of choice to complement electrophysiology studies with a microscopic picture of binding and allosteric regulation. In this chapter, we describe the most effective computational techniques to study VGIC modulation by general anesthetics. We start by reviewing the VGIC conduction cycle, the corresponding set of channel conformations, and the approaches used to model them. We then review the most successful strategies to identify binding sites and estimate binding affinities.
Asunto(s)
Anestésicos Generales/farmacología , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular/tendencias , Canales de Potasio con Entrada de Voltaje/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Regulación Alostérica , Sitios de Unión , Microscopía por Crioelectrón/métodos , Cristalografía por Rayos X/métodos , Activación del Canal Iónico/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Conformación Molecular , Simulación del Acoplamiento Molecular/tendencias , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Resonancia Magnética Nuclear Biomolecular/métodosRESUMEN
BACKGROUND: Fluoroquinolones have been the centre of considerable scientific and clinical interest due to their broad spectrum pharmacological activities. Pefloxacin is an analogue of norfloxacin, which is a 3rd generation of fluoroquinolone antibiotic similar to ciprofloxacin. Pefloxacin is used to treat a variety of bacterial infections like respiratory tract, ear, nose and throat (ENT) infections, skin infections, and urinary tract infections. Hydrazone as a pharmacophore unit that attracts the medicinal chemists because of structure activity relationship (SAR) studies of fluoroquinolones especially the functionality at C-3 position. Consequently, recognition and development of potential ligands specifically for a protein target forms the primary goal in drug discovery process. Among the different theoretical approaches available, Gold and Glide are the molecular docking methods which find application protein ligand studies. In the current study, the DNA gyrase of Staphylococcus aureus has been used as the target protein to understand their possible interactions. METHODS: The crystal structure of DNA gyrase (topoisomerase II) was downloaded from the Protein Data Bank (PDB ID: 2XCS, 3FOE) and molecular docking studies were performed using the docking programs like Gold 3.2 (Genetic Algorithm for Ligand Docking), Glide 5.0 (Grid Based Ligand Docking with Energetic). Melting points were uncorrected and determined in open capillary tubes in a melting point apparatus. TLC was performed on silica gel-G and spotting was done using iodine/ KMnO4 staining or UV-light. The following experimental procedures are representive of the general procedures used to synthesize all compounds. RESULTS: The docking experiments of the title compounds with 2.1 Å crystal structure of DNA gyrase 2XCS, 3FOE using Gold 3.2 and Glide 5.0 is carried out to understand the binding interactions of the novel ligands with the protein, contributing for antibacterial activity. The compounds in general exhibited good binding interactions like H-bonding interaction and π-π interactions which stabilize the protein-ligand complexes and responsible for good fitness scores in both the protocols. CONCLUSION: In summary, a new series of novel pefloxacin hydrazones 5a-5n were studied for their interactions with Staphylococcus aureus DNA gyrase protein by Glide 5.0 and Gold 3.2 molecular docking protocols [PDB IDS: 2XCS, 3FOE]. Among the tested molecules, compound 5g exhibited a good Glide score value of - 7.73 and Glide energy -51.24 with emodel value of -66.16. The nice docking scores of 5g, 5a, 8h, 5m and 5b revealed that these compounds are well accommodated on the active site residues of DNA gyrase enzyme. From the docking study, we have explored the probable binding mode and the binding pattern of compounds 5f, 5l, 5h, 5d, and 5n showed that they strongly interact with in the active site of Staphylococcus aureus of DNA gyrase enzyme. From screening results it is found that compounds having aromatic ring substituted with electron releasing groups are showing potent docking scores and exhibited better fitness than reference compounds CPF and CA4. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development and optimization of the pefloxacin derivatives.
Asunto(s)
Fluoroquinolonas/química , Modelos Moleculares , Simulación del Acoplamiento Molecular/métodos , Animales , Fluoroquinolonas/metabolismo , Humanos , Simulación del Acoplamiento Molecular/tendenciasRESUMEN
BACKGROUND: Lipopeptide synthetases play an important role in the production of lipopeptides. Lipopeptides are molecules made up of peptides and fatty acid moieties and have shown to have a broad range of antimicrobial activity. As infectious diseases have caused severe health problems mainly resulting from the development of antibiotic resistant strains of disease causing microorganisms there is a need of alternatives to antibiotics. The lipopeptide synthetase of the corresponding lipopeptides can be used as template to design these as drugs using computational techniques. OBJECTIVE: The objective of this study was homology modeling and molecular docking of two lipopeptide synthetases, bacillomycin D synthetase and iturin A synthetase, with their ligands as a means of drug design. METHOD: Schrödinger software was used for homology modeling and molecular docking. RESULTS: After the identification of ligands, molecular docking of these ligands with the lipopeptide (bacillomycin and iturin) synthetases was performed. The docking was tested on the parameters of docking score and glide energy. 5 out of 21 ligands were found to dock with bacillomycin D synthetase whereas 8 out of 20 ligands docked with the iturin A synthetase. CONCLUSION: The knowledge of the docking sites and docking characteristics of the lipopeptide synthetases mentioned in the paper with the ligands can provide advantages of high speed and reliability, reduced costs on chemicals and experiments and the ethical issues concerned with the use of animal models for screening of drug toxicity.
Asunto(s)
Lipopéptidos/química , Simulación del Acoplamiento Molecular/métodos , Péptidos Cíclicos/química , Péptidos/química , Péptidos Catiónicos Antimicrobianos , Sitios de Unión/fisiología , Diseño de Fármacos , Ligandos , Ligasas/química , Ligasas/metabolismo , Lipopéptidos/metabolismo , Simulación del Acoplamiento Molecular/tendencias , Péptidos/metabolismo , Péptidos Cíclicos/metabolismoRESUMEN
Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly(glutamic acid) (PG)-dendrimers as nanocarriers of the tumour associated antigens (TAA) MART-1, gp100:44 and gp100:209. Molecular dynamics simulations and docking studies were performed. Nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however, the Frontier Molecular Orbital Theory study evidenced that only 32 of those were available to form covalent bonds. When the number of mannosamines conjugated to dendrimer was increased from 16 to 32, the dendrimer interacted with the receptor with higher affinity. However, 16 mannosamines-NBD-PG-G4-dendrimer was chosen to conjugate TAA for added functionality as no carboxylic end groups were available for further conjugation in the 32 mannosamines-dendrimer. Docking results showed that the majority of TAA-conjugated NBD-PG-G4-dendrimer demonstrated a favourable interaction with mannosamine binding site on mannose receptor, thus constituting a promising tool for TAA targeted delivery. Our in silico approach effectively narrows down the selection of the best candidates for the synthesis of functionalised PG-dendrimers with desired functionalities. These results will significantly reduce the time and efforts required to experimentally synthesise modified dendrimers for optimal antigen delivery.
Asunto(s)
Antígenos de Neoplasias/química , Vacunas contra el Cáncer/química , Dendrímeros/química , Sistemas de Liberación de Medicamentos/tendencias , Ácido Poliglutámico/química , Vacunación/tendencias , Secuencia de Aminoácidos , Antígenos de Neoplasias/administración & dosificación , Antígenos de Neoplasias/metabolismo , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/metabolismo , Computadores Moleculares/tendencias , Dendrímeros/administración & dosificación , Dendrímeros/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Simulación del Acoplamiento Molecular/tendencias , Ácido Poliglutámico/administración & dosificación , Ácido Poliglutámico/genética , Ácido Poliglutámico/metabolismo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Vacunación/métodosRESUMEN
Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors. This review brings new perspectives on structural insights of OSC from different organisms and reveals the broad structural diversity of OSC inhibitors which may help evidence lead compounds for further investigations with various therapeutic applications.
Asunto(s)
Antiinfecciosos/farmacología , Anticolesterolemiantes/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Transferasas Intramoleculares/antagonistas & inhibidores , Modelos Moleculares , Animales , Antiinfecciosos/química , Antiinfecciosos/metabolismo , Anticolesterolemiantes/química , Anticolesterolemiantes/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Antiparasitarios/química , Antiparasitarios/metabolismo , Antiparasitarios/farmacología , Dominio Catalítico , Evaluación Preclínica de Medicamentos/tendencias , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Transferasas Intramoleculares/química , Transferasas Intramoleculares/metabolismo , Conformación Molecular , Simulación del Acoplamiento Molecular/tendencias , Conformación ProteicaRESUMEN
Several members of the short-chain dehydrogenase/reductase (SDR) enzyme family play fundamental roles in adrenal and gonadal steroidogenesis as well as in the metabolism of steroids, oxysterols, bile acids, and retinoids in peripheral tissues, thereby controlling the local activation of their cognate receptors. Some of these SDRs are considered as promising therapeutic targets, for example to treat estrogen-/androgen-dependent and corticosteroid-related diseases, whereas others are considered as anti-targets as their inhibition may lead to disturbances of endocrine functions, thereby contributing to the development and progression of diseases. Nevertheless, the physiological functions of about half of all SDR members are still unknown. In this respect, in silico tools are highly valuable in drug discovery for lead molecule identification, in toxicology screenings to facilitate the identification of hazardous chemicals, and in fundamental research for substrate identification and enzyme characterization. Regarding SDRs, computational methods have been employed for a variety of applications including drug discovery, enzyme characterization and substrate identification, as well as identification of potential endocrine disrupting chemicals (EDC). This review provides an overview of the efforts undertaken in the field of virtual screening supported identification of bioactive molecules in SDR research. In addition, it presents an outlook and addresses the opportunities and limitations of computational modeling and in vitro validation methods.
Asunto(s)
Diseño Asistido por Computadora , Diseño de Fármacos , Disruptores Endocrinos/farmacología , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Animales , Sitios de Unión , Química Farmacéutica/métodos , Química Farmacéutica/tendencias , Biología Computacional , Diseño Asistido por Computadora/tendencias , Bases de Datos de Compuestos Químicos , Disruptores Endocrinos/química , Disruptores Endocrinos/metabolismo , Disruptores Endocrinos/toxicidad , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/toxicidad , Sistemas Especialistas , Ensayos Analíticos de Alto Rendimiento/tendencias , Humanos , Hidroxiesteroide Deshidrogenasas/química , Hidroxiesteroide Deshidrogenasas/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/metabolismo , Aprendizaje Automático , Simulación del Acoplamiento Molecular/tendencias , Conformación Proteica , Especificidad por Sustrato , Toxicología/métodos , Toxicología/tendencias , Estudios de Validación como AsuntoRESUMEN
An integrated computational approach, based on molecular dynamics/mechanics, semi-empirical, and DFT calculations as well as dynamic docking studies, has been employed to gain insight into the mechanism of action of new antimalarial agents characterized by the scaffold of the marine compounds plakortin and aplidinone. The results of this approach show that these molecules, after interaction with Fe(II), likely coming from the heme molecule, give rise to the formation of radical species, that should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The three-dimensional structural requirements necessary for the activity of these new classes of antimalarial agents have been identified and discussed throughout the chapter.
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Antimaláricos/química , Organismos Acuáticos/química , Productos Biológicos/química , Diseño de Fármacos , Simulación del Acoplamiento Molecular/tendencias , Preparaciones Farmacéuticas/química , Animales , Sitios de Unión , Productos Biológicos/uso terapéutico , Química Farmacéutica/tendencias , Simulación por Computador , Evaluación Preclínica de Medicamentos/tendencias , Modelos Químicos , Conformación Molecular , Conformación Proteica , Tecnología Farmacéutica/tendenciasRESUMEN
Molecular docking is a computational method for predicting the placement of ligands in the binding sites of their receptor(s). In this review, we discuss the methodological developments that occurred in the docking field in 2012 and 2013, with a particular focus on the more difficult aspects of this computational discipline. The main challenges and therefore focal points for developments in docking, covered in this review, are receptor flexibility, solvation, scoring, and virtual screening. We specifically deal with such aspects of molecular docking and its applications as selection criteria for constructing receptor ensembles, target dependence of scoring functions, integration of higher-level theory into scoring, implicit and explicit handling of solvation in the binding process, and comparison and evaluation of docking and scoring methods.
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Ligandos , Simulación del Acoplamiento Molecular/tendencias , Receptores de Superficie Celular/química , Algoritmos , Animales , Sitios de Unión , Biología Computacional/métodos , Humanos , Simulación del Acoplamiento Molecular/métodos , Unión Proteica , Receptores de Superficie Celular/metabolismoRESUMEN
The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the strength of binding. We discuss, in detail, methodological developments that occurred in the docking field in 2010 and 2011, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. The main developments in docking in this period, covered in this review, are receptor flexibility, solvation, fragment docking, postprocessing, docking into homology models, and docking comparisons. Several new, or at least newly invigorated, advances occurred in areas such as nonlinear scoring functions, using machine-learning approaches. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design. Where appropriate, we refer readers to exemplar case studies.