RESUMEN
Staphylococcus aureus MurE enzyme catalyzes the addition of l-lysine as third residue of the peptidoglycan peptide moiety. Due to the high substrate specificity and its ubiquitous nature among bacteria, MurE enzyme is considered as one of the potential target for the development of new therapeutic agents. In the present work, induced fit docking (IFD), binding free energy calculation, and molecular dynamics (MD) simulation were carried out to elucidate the inhibition potential of 2-thioxothiazolidin-4-one based inhibitor 1 against S. aureus MurE enzyme. The inhibitor 1 formed majority of hydrogen bonds with the central domain residues Asn151, Thr152, Ser180, Arg187, and Lys219. Binding free-energy calculation by MM-GBSA approach showed that van der Waals (ΔGvdW, -57.30 kcal/mol) and electrostatic solvation (ΔGsolv, -36.86 kcal/mol) energy terms are major contributors for the inhibitor binding. Further, 30-ns MD simulation was performed to validate the stability of ligand-protein complex and also to get structural insight into mode of binding. Based on the IFD and MD simulation results, we designed four new compounds D1-D4 with promising binding affinity for the S. aureus MurE enzyme. The designed compounds were subjected to the extra-precision docking and binding free energy was calculated for complexes. Further, a 30-ns MD simulation was performed for D1/4C13 complex.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/metabolismo , Simulación de Dinámica Molecular , Péptido Sintasas/antagonistas & inhibidores , Péptido Sintasas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Dominio Catalítico , Diseño de Fármacos , Inhibidores Enzimáticos/química , Unión Proteica , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A new series of benzothiazol-2-ylcarbamodithioate functional compounds 5a-f has been designed, synthesized and characterized by spectral data. These compounds were screened for their in vitro antibacterial activity against strains of Staphylococcus aureus (NCIM 5021, NCIM 5022 and methicillin-resistant isolate 43300), Bacillus subtilis (NCIM 2545), Escherichia coli (NCIM 2567), Klebsiella pneumoniae (NCIM 2706) and Psudomonas aeruginosa (NCIM 2036). Compounds 5a and 5d exhibited significant activity against all the tested bacterial strains. Specifically, compounds 5a and 5d showed potent activity against K. pneumoniae (NCIM 2706), while compound 5a also displayed potent activity against S. aureus (NCIM 5021). Compound 5d showed minimum IC50 value of 13.37 µM against S. aureus MurD enzyme. Further, the binding interactions of compounds 5a-f in the catalytic pocket have been investigated using the extra-precision molecular docking and binding free energy calculation by MM-GBSA approach. A 30 ns molecular dynamics simulation of 5d/modeled S. aureus MurD enzyme was performed to determine the stability of the predicted binding conformation.
Asunto(s)
Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Péptido Sintasas/antagonistas & inhibidores , Staphylococcus aureus/enzimología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Benzotiazoles/química , Benzotiazoles/farmacocinética , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Péptido Sintasas/metabolismo , Staphylococcus aureus/efectos de los fármacos , TermodinámicaRESUMEN
The discovery of clinically relevant inhibitors against MurF enzyme has proven to be a challenging task. In order to get further insight into the structural features required for the MurF inhibitory activity, we performed pharmacophore and atom-based three-dimensional quantitative structure-activity relationship studies for novel thiophene-3-carbonitriles based MurF inhibitors. The five-feature pharmacophore model was generated using 48 inhibitors having IC50 values ranging from 0.18 to 663 µm. The best-fitted model showed a higher coefficient of determination (R2 = 0.978), cross-validation coefficient (Q2 = 0.8835) and Pearson coefficient (0.9406) at four component partial least-squares factor. The model was validated with external data set and enrichment study. The effectiveness of the docking protocol was validated by docking the co-crystallized ligand into the catalytic pocket of MurF enzyme. Further, binding free energy calculated by the molecular mechanics generalized Born surface area approach showed that van der Waals and non-polar solvation energy terms are the main contributors to ligand binding in the active site of MurF enzyme. A 10-ns molecular dynamic simulation was performed to confirm the stability of the 3ZM6-ligand complex. Four new molecules are also designed as potent MurF inhibitors. These results provide insights regarding the development of novel MurF inhibitors with better binding affinity.
Asunto(s)
Péptido Sintasas/química , Infecciones Neumocócicas/tratamiento farmacológico , Streptococcus pneumoniae/enzimología , Tiofenos/química , Sitios de Unión/efectos de los fármacos , Dominio Catalítico/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Péptido Sintasas/antagonistas & inhibidores , Péptido Sintasas/genética , Infecciones Neumocócicas/enzimología , Infecciones Neumocócicas/microbiología , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/patogenicidad , Tiofenos/metabolismo , Tiofenos/farmacologíaRESUMEN
Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa 4/química , Pirimidinas/química , Relación Estructura-Actividad Cuantitativa , Análisis de los Mínimos Cuadrados , Simulación de Dinámica Molecular , Reproducibilidad de los Resultados , TermodinámicaRESUMEN
Alanine racemase is a fold type III PLP-dependent amino acid racemase enzyme catalysing the conversion of l-alanine to d-alanine utilised by bacterial cell wall for peptidoglycan synthesis. As there are no known homologs in humans, it is considered as an excellent antibacterial drug target. The standard inhibitors of this enzyme include O-carbamyl-d-serine, d-cycloserine, chlorovinyl glycine, alaphosphin, etc. d-Cycloserine is indicated for pulmonary and extra pulmonary tuberculosis but therapeutic use of drug is limited due to its severe toxic effects. Toxic effects due to off-target affinities of cycloserine and other substrate analogs have prompted new research efforts to identify alanine racemase inhibitors that are not substrate analogs. In this review, an updated status of known inhibitors of alanine racemase enzyme has been provided which will serve as a rich source of structural information and will be helpful in generating selective and potent inhibitor of alanine racemase.
Asunto(s)
Alanina Racemasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Alanina Racemasa/metabolismo , Animales , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura MolecularRESUMEN
GyrB and ParE are type IIA topoisomerases and found in most bacteria. Its function is vital for DNA replication, repair and decatenation. The highly conserved ATP-binding subunits of DNA GyrB and ParE are structurally related and have been recognized as prime candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, no natural product or small molecule inhibitors targeting ATPase catalytic domain of both GyrB and ParE enzymes have succeeded in the clinic. Moreover, no inhibitors of these enzymes with broad-spectrum antibacterial activity against Gram-negative pathogens have been reported. Availability of high resolution crystal structures of GyrB and ParE made it possible for the design of many different classes of inhibitors with dual mechanism of action. Among them benzimidazoles, benzothiazoles, thiazolopyridines, imidiazopyridazoles, pyridines, indazoles, pyrazoles, imidazopyridines, triazolopyridines, pyrrolopyrimidines, pyrimidoindoles as well as related structures are disclosed in literatures. Unfortunately most of these inhibitors are found to be active against Gram-positive pathogens. In the present review we discuss about studies on novel dual targeting ATPase inhibitors.
Asunto(s)
Girasa de ADN/efectos de los fármacos , Topoisomerasa de ADN IV/efectos de los fármacos , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa/farmacología , Secuencia de Aminoácidos , Aminopiridinas/farmacología , Antibacterianos/farmacología , Barbitúricos/farmacología , Bencimidazoles/farmacología , Fluoroquinolonas/farmacología , Indazoles/farmacología , Isoxazoles , Morfolinas , Organofosfatos/farmacología , Oxazolidinonas , Profármacos/farmacología , Pirazoles/farmacología , Pirroles/farmacología , Pirrolidinas/farmacología , Pirrolidinonas/farmacología , Quinazolinonas/farmacología , Quinolinas/farmacología , Compuestos de Espiro/farmacología , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a potential threat globally since it is associated with high morbidity and mortality. In addition, the ability of MRSA to develop resistance and adapt to various environments makes it exceptional from other bacterial strains. Effective management is best determined by the site of infection. OBJECTIVES: This study aims to summarize and assess the epidemiology of MRSA, resistance, detection of MRSA in humans, animals, and food products, treatment employed, and combination therapy. METHODS: For the present review, we collected data from PubMed, Embase, Web of Science, BioMed Central, Medline, Encyclopedia of Life Sciences, Scopus, Cochrane Library, and ScienceDirect that report the epidemiology of MRSA, drug resistance in MRSA, spread of MRSA infection, diagnosis of infection, existing and emerging remedies of MRSA infections. Collected data were analyzed and represented in this article with the help of Figures and Tables. RESULTS: S. aureus resistance to vancomycin is because of genetic adaptation and also due to the widespread and indiscriminate use of antibiotics in the treatment of MRSA infection. Specifically, infections related to vancomycin-resistant S. aureus are life-threatening and difficult to treat. MRSA epidemiology with the recognition of community-acquired-MRSA transmission between livestock and humans is also reported and is alarming. Multiple studies suggested that early detection of MRSA colonization and elimination of carriage can help reduce the risk of subsequent infection. Specifically, PCR-based screening from different body sites offers the highest overall sensitivity for the detection of MRSA carriage. CONCLUSION: Screening novel mutants and methods of transmission in each environment will assist in managing MRSA. Further, effective MRSA control in all clinical setups is required with the avoidance of uncontrolled antibiotic usage.
RESUMEN
Bacterial infections are a major cause of mortality and morbidity in humans throughout the world. Infections due to resistant bacterial strains such as methicillin-resistant Staphyloccocusaureus vancomycin, resistant Enterococci, Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium are alarming. Hence the development of new antibacterial agents, which act via a novel mechanism of action, became a priority in antibacterial research. One such approach to overcome bacterial resistance is to target novel protein and develop antibacterial agents that act via different mechanisms of action. Bacterial GlmU is one such bifunctional enzyme that catalyzes the two consecutive reactions during the biosynthesis of uridine 5'-diphospho-Nacetylglucosamine, an essential precursor for the biosynthesis of bacterial cell wall peptidoglycan. This enzyme comprises two distinct active sites; acetyltransferase and uridyltransferase and both these active sites act independently during catalytic reactions. GlmU is considered an attractive target for the design and development of newer antibacterial agents due to its important role in bacterial cell wall synthesis and the absence of comparable enzymes in humans. Availability of three dimensions X-crystallographic structures of GlmU and their known catalytic mechanism from different bacterial strains have instigated research efforts for the development of novel antibacterial agents. Several GlmU inhibitors belonging to different chemical classes like 2- phenylbenzofuran derivative, quinazolines, aminoquinazolines, sulfonamides, arylsulfonamide, D-glucopyranoside 6-phosphates, terreic acid, iodoacetamide, N-ethyl maleimide, and Nethylmaleimide etc., have been reported in the literature. In the present review, we present an update on GlmU inhibitors and their associated antibacterial activities. This review may be useful for the design and development of novel GlmU inhibitors with potent antibacterial activity.
Asunto(s)
Antibacterianos , Inhibidores Enzimáticos , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Catálisis , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/químicaRESUMEN
BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.
Asunto(s)
COVID-19 , Humanos , Ligandos , Simulación del Acoplamiento Molecular , SARS-CoV-2 , Simulación de Dinámica MolecularRESUMEN
Alanine racemase is a pyridoxal-5'-phosphate dependent bacterial enzyme that provides the essential peptidoglycan precursor D-alanine, utilized for cell wall synthesis. This enzyme is ubiquitous throughout bacteria, including Mycobacterium tuberculosis, making it an attractive target for antibacterial drug discovery. We investigated the binding mode of twenty five reported Mycobacterium tuberculosis alanine racemase inhibitors. The results obtained from molecular docking studies emphasized the importance of inhibitor interaction with Lys42, Tyr46, Arg140, His172 and Tyr175 residues at the catalytic binding pocket of alanine racemase enzyme. The predicted binding free energies showed that van der Waals and nonpolar solvation interactions are the driving force for binding of inhibitors. Molecular dynamics simulation studies of four such inhibitor-alanine racemase systems were further explored to study the inhibition mechanism. The quantum chemical parameters calculated at the B3LYP/6-31G**++ level of theory indicated that the inhibitors must have low values of the lowest unoccupied molecular orbital energy and high values of electrostatic potential for stronger interactions. We expect that this study can provide significant theoretical guidance for design of potent Mycobacterium tuberculosis alanine racemase inhibitors in future.
Asunto(s)
Alanina Racemasa , Mycobacterium tuberculosis , Alanina/química , Alanina Racemasa/química , Alanina Racemasa/metabolismo , Antibacterianos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mycobacterium tuberculosis/metabolismoRESUMEN
BACKGROUND: The widespread hazardous issue of antibiotics resistance can be overcome by the development of target based potent antibacterial agents. Filamentous temperature-sensitive mutant Z (FtsZ), a simpler structural prokaryotic homolog of eukaryotic cytoskeletal tubulin, was considered as a competent target in antibacterial drug discovery. OBJECTIVE: The purpose of the present work is to evaluate the antitubercular activity of virtual hits by funnel-shaped filtering with glide docking, followed by MM-GBSA binding energy and molecular dynamics simulation. Pharmacokinetics and biochemical activity of the computationally screened virtual hits have been studied to focus their potential to inhibit the bacterial cell division. METHODS: The docking study was performed against the crystal structure of Staphylococcus aureus and Mycobacterium tuberculosis FtsZ protein with the hits obtained from High Throughput Virtual Screening using the Glide module in Schrodinger. ADME profile and 50 ns molecular dynamics simulation studies were performed using the Schrödinger suite. The minimal inhibitory concentration of the test compounds was determined by the colorimetric method by the Resazurin Microtiter plate Assay. RESULTS: The binding of hit molecules T5427054 and 6M356S was mainly supported by van der Waals interaction and an electrostatic component of solvation energy computed by the MM-GBSA method. 50 ns MD simulation built stability and dynamic property of the best-docked complex T5427054/2Q1Y. Both the hit molecules displayed antimycobacterial activity with minimal inhibitory concentration 500 µg/mL. CONCLUSION: In this study, it is found that new screened hit molecules with better theoretical results could be preferred to use as antimycobacterial agents, and further their structural modification might be improved antimycobacterial properties of hit molecules.
Asunto(s)
Simulación de Dinámica Molecular , Mycobacterium tuberculosis , Antituberculosos/farmacología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Unión ProteicaRESUMEN
ATP dependent ParE enzyme is as an attractive target for the development of antibacterial agents. Atom based 3D-QSAR model AADHR.187 was developed based on the thirty eight Escherichia coli ParE inhibitors. The generated model showed statistically significant coefficient of determinations for the training (R2â¯=â¯0.985) and test (R2â¯=â¯0.86) sets. The cross-validated correlation coefficient (q2) was 0.976. The utility of the generated model was validated by the enrichment study. The model was also validated with structurally diverse external test set of ten compounds. Contour plot analysis of the generated model unveiled the chemical features necessary for the E. coli ParE enzyme inhibition. Extra-precision docking result revealed that hydrogen bonding and ionic interactions play a major role in ParE protein-ligand binding. Binding free energy was computed for the data set inhibitors to validate the binding affinity. A 30-ns molecular dynamics simulation showed high stability and effective binding of inhibitor 34 within the active site of ParE enzyme. Using the best fitted model AADHR.187, pharmacophore-based high-throughput virtual screening was performed to identify virtual hits. Based on the above studies three new molecules are proposed as E. coli ParE inhibitors with high binding affinity and favourable ADME properties.
Asunto(s)
Proteínas de Escherichia coli/antagonistas & inhibidores , Escherichia coli/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Simulación por Computador , LigandosRESUMEN
In an effort to face the multiple drug-resistant bacteria, various approaches have been discovered to design potent compounds and search new targets through computational design tools. With an aim to identify selective inhibitors against filamentous temperature-sensitive mutant Z (FtsZ), a library of Phase database compounds have been virtually screened. High-throughput virtual screening of compounds against Staphylococcal epidermidis FtsZ protein (4M8I) was performed using three sequential docking modes like high-throughput virtual screening, Glide standard precision, followed by Glide extra precision. Four top-ranked compounds were selected from molecular mechanics-generalized Born surface area (MM-GBSA) binding energy with better predicted free binding energies of - 89.309, - 54.382, - 53.667, and - 52.133 kcal/mol, respectively. It is also showed that the contribution of van der Waals and electrostatic solvation energy terms are playing a major part to make the hit molecule (T6288784) binding to S. epidermidis FtsZ protein. The result of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy gap analysis predicts the molecular reactivity and stability of hit molecules. Subsequently, Lipinski's rule of five and properties of absorption, distribution, metabolism, and excretion (ADME) were to calculate their bioavailability. The average binding energy - 9.67 kcal/mol of the best proposed hit molecule (T6288784) was found with half-maximal inhibitory concentration (IC50) value to be 75.53 nM. A 15-ns molecular dynamics simulation study revealed the stable conformation of hit molecule. On a wide-range research discipline, in silico studies of our proposed compound confirm promising results and can be successfully used towards the development of novel FtsZ inhibitor with better binding affinity. Graphical Abstract.
RESUMEN
FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 µM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R2 = .8319), cross validated coefficient (Q2 = .6213) and a high Fisher ratio (F = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (R2 = .83) and test set (R2 = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD-ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.
Asunto(s)
Proteínas Bacterianas/química , Benzamidas/farmacología , Proteínas del Citoesqueleto/química , Farmacorresistencia Bacteriana Múltiple/genética , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Benzamidas/química , Sitios de Unión , Dominio Catalítico , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas del Citoesqueleto/genética , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas/efectos de los fármacos , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad Cuantitativa , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/patogenicidadRESUMEN
The binding modes of well known MurD inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. The docking results of inhibitors 1-30 revealed similar mode of interaction with Escherichia coli-MurD. Further, residues Thr36, Arg37, His183, Lys319, Lys348, Thr321, Ser415 and Phe422 are found to be important for inhibitors and E. coli-MurD interactions. Our docking procedure precisely predicted crystallographic bound inhibitor 7 as evident from root mean square deviation (0.96Å). In addition inhibitors 2 and 3 have been successfully cross-docked within the MurD active site, which was pre-organized for the inhibitor 7. Induced fit best docked poses of 2, 3, 7 and 15/2Y1O complexes were subjected to 10ns MD simulations to determine the stability of the predicted binding conformations. Induce fit derived docked complexes were found to be in a state of near equilibrium as evident by the low root mean square deviations between the starting complex structure and the energy minimized final average MD complex structures. The results of molecular docking and MD simulations described in this study will be useful for the development of new MurD inhibitors with high potency.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Ácido Glutámico/análogos & derivados , Ácido Glutámico/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Péptido Sintasas/antagonistas & inhibidores , Termodinámica , Inhibidores Enzimáticos/química , Ácido Glutámico/química , Péptido Sintasas/metabolismoRESUMEN
Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrödinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2 )= .9949), cross validation coefficient (Q(2 )= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10-ns MD simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Fosfodiesterasa 4/química , Relación Estructura-Actividad Cuantitativa , Sitios de Unión , Dominio Catalítico , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Inhibidores de Fosfodiesterasa 4/farmacología , Reproducibilidad de los ResultadosRESUMEN
Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study pharmacophore and atom based 3D-QSAR studies were carried out for pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues. A five point pharmacophore model was developed using 52 molecules having pIC50 values ranging from 9.959 to 3.939. The best predictive pharmacophoric hypothesis AHHRR.3 was characterized by survival score (2.944), cross validated (r(2) = 0.8147), regression coefficient (R(2) = 0.9545) and Fisher ratio (F =173) with 4 component PLS factor. Results explained that one hydrogen bond acceptor, two aromatic rings and two hydrophobic groups are crucial for the PDE4 inhibition. The docking studies of all selected inhibitors in the active site of PDE4 showed crucial hydrogen bond interactions with Asp392, Asn395 Tyr233, and Gln443 residues. The pharmacophoric features R15 and R16 exhibited π-π stacking with His234, Phe414, and Phe446 residues. The generated model was further validated by carrying out the decoy test. The binding free energies of these inhibitors in the catalytic domain of 1XMU were calculated by the molecular mechanics/generalized Born surface area VSGB 2.0 method. The results of molecular dynamics simulation confirmed the extra precision docking-predicted priority for binding sites, the accuracy of docking, and the reliability of active conformations. Pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues in this study showed lower binding affinity toward PDE3A in comparison to PDE4. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. Graphical Abstract Pyrozolo[1,5-a]pyridines/4,4-dimethylpyrazolones.
Asunto(s)
Inhibidores de Fosfodiesterasa 4/química , Pirazolonas/química , Sitios de Unión , Dominio Catalítico , Descubrimiento de Drogas , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piridinas/química , Relación Estructura-Actividad CuantitativaRESUMEN
Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B.
RESUMEN
In the present study, a series of benzothiazol derivatives 3a-l containing pyrazolo[3,4-d]pyrimidine moiety at the second position were synthesized and characterized by analytical and spectral data. The compounds were tested for their in vitro antimicrobial activity. Compounds 1-(1,3-benzothiazol-2- yl)-3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidine (3a), 1- (1,3-benzothiazol-2-yl)-4-(4-chlorophenyl)-3-methyl-1H-pyrazolo[ 3,4-d]pyrimidine (3d) and 1-(1,3-benzothiazol-2-yl)- 3-methyl-4-substituted phenyl-1H-pyrazolo[3,4-d]pyrimidines (3h-j) showed significant inhibitory activity against P. aeruginosa whereas compounds 1-(1,3-benzothiazol-2-yl)-4- (2-chlorophenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (3b), 2-[1-(1,3-benzothiazol-2-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl]phenol (3e), 1-(1,3-benzothiazol-2-yl)-4-(3,4-dimethoxyphenyl)- 3-methyl-1H-pyrazolo[3,4-d]pyrimidine (3h), 4-[1-(1,3-benzothiazol-2-yl)-3-methyl-1H-pyrazolo[3,4-d]pyri midin-4-yl]-N,N-dimethylaniline (3j) and 1-(1,3-benzothiazol- 2-yl)-3-methyl-4-[2-phenylvinyl]-1H-pyrazolo[3,4-d]pyrimidine (3k) were found to be active against C. albicans. Some of these synthesized compounds were evaluated for their in vivo acute toxicity, analgesic, anti-inflammatory, and ulcerogenic actions. The tested compound 4-[1-(1,3-benzothiazol- 2-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N, N-dimethylaniline (3j) exhibited maximum analgesic and anti-inflammatory activities. Compounds 1-(1,3-benzothiazol- -2-yl)-3-methyl-4-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidine (3i) and 3j showed a significant gastrointestinal protection compared to the standard drug diclofenac sodium.
Asunto(s)
Benzotiazoles/química , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Bacterias/efectos de los fármacos , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Femenino , Hongos/efectos de los fármacos , Masculino , Ratones , Pirazoles/química , Pirimidinas/química , Ratas , Ratas WistarRESUMEN
2-Mercaptobenzothiazoles are an important class of bioactive and industrially important organic compounds. These compounds are reported for their antimicrobial and antifungal activities, and are subsequently highlighted as a potent mechanism-based inhibitor of several enzymes like acyl coenzyme A cholesterol acyltransferase, monoamine oxidase, heat shock protein 90, cathepsin D, and c-Jun N-terminal kinases. These derivatives are also known to possess antitubercular, anti-inflammatory, antitumor, amoebic, antiparkinsonian, anthelmintic, antihypertensive, antihyperlipidemic, antiulcer, chemoprotective, and selective CCR3 receptor antagonist activity. This present review article focuses on the pharmacological profile of 2-mercaptobenzothiazoles with their potential activities.