Some bis (3-(4-nitrophenyl)acrylamide derivatives: Synthesis, characterization, DFT, antioxidant, antimicrobial properties, molecular docking and molecular dynamics simulation studies-Supplemenntary data

Alzheimer's disease, which is a progressive neurologic disorder, is the most common form of dementia. Although there are various treatment options for Alzheimer’s disease, there is no definite treatment for this disease yet. In this study it was aimed to investigate the treatment potentials of three bis(3-(4-nitrophenyl)acrylamide) derivatives, two of which are known and one is new, for Alzheimer's disease. The study consists of three parts; in the first part of the study, synthesis and characterization studies of the investigated compounds were carried out. In the characterization of the compounds, IR, 1H-NMR, 13C-NMR, LC-MS and elemental analysis techniques were used. In the second part of the study, the compounds were investigated computationally with the assistance of various computational techniques including density functional theory (DFT) calculations, molecular docking and molecular dynamics simulations. In this part, binding free energy calculations were also performed on the investigated compounds. Results of computational studies showed that synthesized compounds interacted with AChE effectively and can be promising structures as AChE inhibitors. In the last part of the study, antioxidant and antimicrobial properties of the compounds were investigated. Antioxidant activities were determined by DPPH? and ABTS?? radical scavenging methods. According to the DPPH? test, the most active compound was found to be 2, while the most active compound was found to be 3 according to the ABTS? test, showing that these methods for antioxidant assay were not significantly correlated with each other. On the other hand, the results of the antimicrobial activity tests showed that compound 3 was the most active compound, which exhibited both antioxidant and antimicrobial activity.

Some bis (3-(4-nitrophenyl)acrylamide derivatives: Synthesis, characterization, DFT, antioxidant, antimicrobial properties, molecular docking and molecular dynamics simulation studies

Alzheimer's disease, which is a progressive neurologic disorder, is the most common form of dementia. Although there are various treatment options for Alzheimer’s disease, there is no definite treatment for this disease yet. In this study it was aimed to investigate the treatment potentials of three bis(3-(4-nitrophenyl)acrylamide) derivatives, two of which are known and one is new, for Alzheimer's disease. The study consists of three parts; in the first part of the study, synthesis and characterization studies of the investigated compounds were carried out. In the characterization of the compounds, IR, 1H-NMR, 13C-NMR, LC-MS and elemental analysis techniques were used. In the second part of the study, the compounds were investigated computationally with the assistance of various computational techniques including density functional theory (DFT) calculations, molecular docking and molecular dynamics simulations. In this part, binding free energy calculations were also performed on the investigated compounds. Results of computational studies showed that synthesized compounds interacted with AChE effectively and can be promising structures as AChE inhibitors. In the last part of the study, antioxidant and antimicrobial properties of the compounds were investigated. Antioxidant activities were determined by DPPH? and ABTS?? radical scavenging methods. According to the DPPH? test, the most active compound was found to be 2, while the most active compound was found to be 3 according to the ABTS? test, showing that these methods for antioxidant assay were not significantly correlated with each other. On the other hand, the results of the antimicrobial activity tests showed that compound 3 was the most active compound, which exhibited both antioxidant and antimicrobial activity.

Free energy perturbation (FEP)-guided scaffold hopping

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.

Predicting complexation performance between cyclodextrins and guest molecules by integrated machine learning and molecular modeling techniques

Most pharmaceutical formulation developments are complex and ideal formulations are generally obtained after extensive experimentation. Machine learning is increasingly advancing many aspects in modern society and has achieved significant success in multiple subjects. Current research demonstrated that machine learning can be adopted to build up high-accurate predictive models in drugs/cyclodextrins (CDs) systems. Molecular descriptors of compounds and experimental conditions were employed as inputs, while complexation free energy as outputs. Results showed that the light gradient boosting machine provided significantly improved predictive performance over random forest and deep learning. The mean absolute error was 1.38 kJ/mol and squared correlation coefficient was 0.86. The evaluation of relative importance of molecular descriptors further demonstrated the key factors affecting molecular interactions in drugs/CD systems. In the specific ketoprofen-CD systems, machine learning model showed better predictive performance than molecular modeling calculation, while molecular simulation could provide structural, dynamic and energetic information. The integration of machine learning and molecular simulation could produce synergistic effect for interpreting and predicting pharmaceutical formulations. In conclusion, the developed predictive models were able to quickly and accurately predict the solubilizing capacity of CD systems. Current research has taken an important step toward the application of machine learning in pharmaceutical formulation design.

Molecular recognition mechanism and motion of HCV NS3/4A protease with Faldaprevir analogue / 生物工程学报

Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.4 ns molecular dynamics simulation of the complex consists of HCV NS3/4A protease and FAM was conducted. The key amino acid residues for interaction and the binding driving force for the molecular recognition between the protease and FAM were identified from the hydrogen bonds and binding free energy analyses. With the driving force of hydrogen bonds and van der Waals, FAM specifically bind to the active pocket of HCV NS3/4A protease, including V130-S137, F152-D166, D77-D79 and V55, which agreed with the experimental data. The effect of R155K, D168E/V and V170T site-directed mutagenesis on FAM molecular recognition was analyzed for their effect on drug resistance, which provided the possible molecular explanation of FAM resistance. Finally, the system conformational change was explored by using free energy landscape and conformational cluster. The result showed four kinds of dominant conformation, which provides theoretical basis for subsequent design of Faldaprevir analogue inhibitors based on the structure of HCV NS3/4A protease.

Molecular evolution of carbapenemases KPC-12 and molecular docking analysis of β-lactams / 中华临床感染病杂志

Objective To analyze molecular evolution of carbapenemase KPC-12 and its binding free energies with β-lactams.Methods Class A beta-lactamases were divided into 2 clusters:those with carbapenemase activities and those without.Minimum Evolution method in MEGA4.1 software was used to analyze molecular evolution of class A beta-lactamases with carbapenemase activity,including KPC-2 to KPC-13,SFC-1,SME-1,IMI-1,NMC-A,and class A beta-lactamases without carbapenemase activity,including TEM-1,SHV-1.Then,tertiary structure of KPC-12 was predicted by homology modeling as reported in SWISS-MODEL database depending on tertiary structure of KPC-2.Moreover,DOCK module in ArgusLab 4.1 software was used to perform molecular docking of KPC-12 to 10 kinds of beta-lactams substrates,and the binding free energies (△ G) were calculated.Results Molecular evolution between KPC-12 and KPC-2 was the closest.The top three decline in binding free energies of β-lactams were penicillin G sodium salt (△G =-8.45149 kcal/mol),ertapenem (△G =-8.36383 kcal/mol) and ampicillin (△G =-8.19326 kcal/mol),while the last two decline in binding free energies of β-lactams were aztreonam (△G =-6.50614 kca]/mol) and clavulanic acid (△G =-6.88533 kcal/mol).Conclusion Carbapenemase KPC-12 has high catalytic activities to penicillin G sodium salt,ertapenem and ampicillin,while has low catalytic activities to aztreonam and clavulanic acid.

Influence of Mg2+ ions on the interaction between 3,5-dicaffeoylquinic acid and HTLV-I integrase / Influencia de los iones Mg+2 sobre la interacción entre el ácido 3,5- dicafeoilquínico y la integrasa del HTLV-I / Influência dos íons Mg2+ sobre a interação entre o ácido 3,5-dicafeoilquínico e a integrase do HTLV-I

Objective. Using molecular simulation, we studied the influence of Mg2+ ions on the binding mode of HTLV-I Integrase (IN) catalytic domain (modeled by homology) with the 3,5- Dicaffeoylquinic Acid (DCQA). HTLV-I Integrase homology model was built using template-like crystallographic data of the IN catalytic domain solved for Avian Sarcoma Virus (VSA, pdb: 1VSD). Materials and methods. In order to analyze the role of Mg2+ in the interaction or coupling between 3,5-DCQA and Integrase, three models were created: i) in the absence of Mg2+ ions, ii) with a Mg2+ ion coordinated at Asp15 and Asp72 and iii) model with two Mg2+ ions coordinated at Asp15-Asp72 and Asp72-Glu108. Coupling force and binding free energy between 3,5-DCQA and HTLV-I IN were assessed in the three models. Results. The lowest docking score and free energy binding were obtained for the second model. Mg2+ ion strongly affected the coupling of the inhibitor 3,5-DCQA with HTLV-I catalytic domain of Integrase, thus revealing a strong interaction in the ligand-protein complex regardless of the ligand-catalytic interaction sites for all three models. Conclusion. Altogether, these results strengthen the hypothesis that the presence of one Mg2+ ion could enhance the interaction in the complex by decreasing free energy, therefore increasing the affinity. Moreover, we propose 3,5-DCQA as an important pharmacophore in the rational design of new antiretroviral drugs.

Objetivo: Usando simulación molecular, estudiamos la influencia de los iones Mg2+ en la interacción del dominio catalítico de la integrasa HTLV-I (IN) (modelado por homología) con el ácido 3,5-Dicafeoilquínico (DCQA). Materiales y métodos. El modelo por homología de la HTLV-I IN fue construido usando como molde la estructura cristalina de la IN del virus del sarcoma aviar (VSA, pdb: 1VSD). Para analizar el rol de los iones Mg2+ en la interacción con el DCQA y la integrasa, tres modelos fueron creados: i) en ausencia de iones Mg2+, ii) con un ion Mg2+ coordinado con Asp15 y Asp72 y iii) con dos iones Mg2+ coordinados con Asp15-Asp72 y Asp72-Glu108. Las fuerzas de interacción y la energía libre de unión entre el DCQA y la HTLV-I IN fueron calculadas en los tres modelos. Resultados. El puntaje más bajo en el docking y la menor energía libre fueron obtenidos para el modelo con un solo ion de Mg2+. El Mg2+ afecta fuertemente el acoplamiento del inhibidor DCQA con el dominio catalítico de la HTLV-I IN, revelando una fuerte interacción entre el complejo ligando-proteína que es independiente del sitio catalítico de los tres modelos usados. Conclusión. Los resultados sugieren que la presencia de un ion de Mg² + podría incrementar la interacción en el complejo debido a la disminución de la energía libre, intensificando así la afinidad. Por lo que, proponemos al DCQA como farmacóforo para el diseño de drogas antiretrovirales.

Objetivo. Usando simulação molecular, estudamos a influência dos íons Mg2+ na interação do domínio catalítico da integrase HTLV-I (IN) (modelado por homologia) com o ácido 3,5-dicafeoilquínico (3,5-diCQA). Materiais e métodos. O modelo de homologia da HTLV-I IN foi construído utilizando como fôrma a estrutura cristalina da IN de vírus do sarcoma aviário (VSA, pdb: 1VSD). Para analisar o papel dos íons Mg2+ na interação com o 3,5-diCQA e a integrase, três modelos foram criados: i) na ausência de íons Mg2+, ii) com um íon Mg2+ coordenado com Asp15 e Asp72 e, iii) com dois íons Mg2+ coordenados com Asp15-Asp72 e Asp72-Glu108. As forças de interação e a energia livre de ligação entre o 3,5-diCQA e a HTLV-I IN foram calculadas nos três modelos. Resultados. A pontuação mais baixa no docking e a menor energia livre foram obtidas para o modelo com um único íon de Mg2+. O Mg2+ afeta fortemente o acoplamento do inibidor 3,5-diCQA com o domínio catalítico da HTLV-I IN, revelando uma forte interação entre o complexo ligando-proteína que é independente do sítio catalítico dos três modelos utilizados. Conclusão. Os resultados sugerem que a presença de um íon Mg2+ poderia aumentar a interação no complexo devido à diminuição da energia livre, aumentando assim a afinidade. Assim, propomos ao 3,5-diCQA como farmacóforo para a fabricação de medicamentos antirretrovirais.

In silico analysis of peptide binding features of HLA-B*4006.

HLA-B*4006 is the most common allele amongst Indians. It belongs to the ‘HLA-B44 supertype’ family of alleles that constitute an important component of the peptide binding repertoire in populations world over. Its peptide binding characteristics remain poorly examined. The amino acid sequence and structural considerations suggest a small, poorly hydrophobic ‘F’ pocket for this allele that may adversely affect the interaction with the C terminal residue of the antigenic peptide. Contribution of auxiliary anchor residues (P3) of the peptide has also been indicated. To examine these aspects by in silico analysis, HLA-B*4001, 4002, and 4006 alleles were modeled using HLA-B*4402 as a template. Eleven peptides, known to bind alleles of this family, were used for docking and molecular dynamics studies. Interaction between the amino group (main-chain) of P3 residue and Tyr99 of the alleles was seen in majority of peptide-complexes. Hydrophobic interactions between Tyr7 and Tyr159 with N terminal residues of the peptide were also seen in all the complexes. Replacement of Trp95 by leucine in HLA-B*4006 resulted in reduction of binding free energy in 8 out of 9 complexes. In summary, the analysis of the modeled structures and HLA-peptide complexes strongly supports the adverse effect of Trp95 at pocket F and the possible role of the third residue of the antigenic peptide as an auxiliary anchor in HLA-B*4006 peptide complexes. In the light of suggested promiscuous peptide binding pattern and association with risk for tuberculosis/HIV for this allele, the ascertainment of the predicted effects of Trp95 and role of P3 residue as an auxiliary anchor by this preliminary in silico analysis thus helps define direction of the further studies.

Molecular evolution and binding free energy analysis of substrates of cephalosporinase ADC-57 / 中华临床感染病杂志

Objective To analyze molecular evolution and binding free energies of cephalosporinase ADC-57.Methods Minimum Evolution method in MEGA 5.0 was used to analyze molecular evolution of cephalosporinase ADC-57 and other 19 kinds of beta-lactamases.Tertiary structure of ADC-57 was predicted by homology modeling referring to tertiary structure of CMY-2.The molecular docking of ADC-57 to 11kinds of beta-lactams substrates was performed using DOCK module in ArgusLab 4.1and the binding free energies (△G) was calculated.Results ADC-57,CMY-2,DHA-1,ADC-7,ADC-56 were all belong to class C beta-lactamase,and molecular evolution between ADC-57 and ADC-56 was closest.The top three antibiotics with declining binding free energy of beta-lactams were ertapenem,cefoxitin and ceftazidine,while the last two were clavulanic acid and aztreonam.Conclusions Catalytic activities of cephalosporinase ADC-57 to ertapenem,cefoxitin and ceftazidine are high,while to clavulanic acid and aztreonam are low. Hydrolytic activities of enzyme to beta-lactams (substrates) can be analyzed by molecular docking.

Molecular evolution and binding free energy analysis on substrates of KPC carbapenemases / 中华临床感染病杂志

Objective To analyze molecular evolution and binding free energies in substrates of KPC-2,KPC-5 and KPC-10 carbapenemases.Methods Minimum Evolution method in MEGA 4.1 was used to analyze molecular evolution of KPC-2,KPC-5 and KPC-10 carbapenemases,Dock module in ArgusLab 4.1 was used to perform molecular docking of these 3 carbapenemases to 10 kinds of β-lactams substrates,and calculate binding free energies(△G).Results Ambler Class A β-lactamases with carbapenemase activities were grouped in the same cluster and had good conservation,while ordinary Ambler Class A β-lactamases without carbapenemase activities were groupod in the other cluster.Binding free energies of KPC-2,KPC-5 and KPC-10 carbapenemases were lower to carbapenem antibiotics than the thirdgeneration cephalosporins,while binding free energies to aztreonam and clavulanic acid were of comparatively higher levels.Conclusion Catalytic activities of KPC to carbapenem antibiotics are higher than those to the third-generation cephalosporins,but the activities to aztreonam and clavulanic acid are low.