Pub Date : 2023-08-30DOI: 10.3390/biophysica3030034
D. Prikule, V. F. Prikuls, A. Potrivailo, Anna Kamavosyan
In modern dentistry, the problem of the prevention and treatment of peri-implantitis is relevant. Proposed methods of treating patients with peri-implantitis do not stop the pathological process with the possibility of achieving long-term remission. Liposomal complexes with dihydroquercetin make it possible to influence the pathogenetic links of the inflammatory process in periodontal tissues with the prospect of normalizing blood circulation and regeneration processes in the affected area. It has been established that the complex simultaneous effect of low-intensity laser radiation and a pharmaceutical (laserophoresis) provides the possibility of more significant penetration of the drug components into periodontal tissues. The study of the laserophoresis of the liposomal complex with dihydroquercetin in the treatment of patients with peri-implantitis is relevant. However, in the modern literature, there is a lack of studies on the effect of low-intensity laser radiation on the pharmaceutical structure of drugs based on the above-mentioned basis.
{"title":"Experimental Determination of the Stability of the «Flamena» Gel Pharmacological Structure under the Influence of Low-Intensity Laser Radiation","authors":"D. Prikule, V. F. Prikuls, A. Potrivailo, Anna Kamavosyan","doi":"10.3390/biophysica3030034","DOIUrl":"https://doi.org/10.3390/biophysica3030034","url":null,"abstract":"In modern dentistry, the problem of the prevention and treatment of peri-implantitis is relevant. Proposed methods of treating patients with peri-implantitis do not stop the pathological process with the possibility of achieving long-term remission. Liposomal complexes with dihydroquercetin make it possible to influence the pathogenetic links of the inflammatory process in periodontal tissues with the prospect of normalizing blood circulation and regeneration processes in the affected area. It has been established that the complex simultaneous effect of low-intensity laser radiation and a pharmaceutical (laserophoresis) provides the possibility of more significant penetration of the drug components into periodontal tissues. The study of the laserophoresis of the liposomal complex with dihydroquercetin in the treatment of patients with peri-implantitis is relevant. However, in the modern literature, there is a lack of studies on the effect of low-intensity laser radiation on the pharmaceutical structure of drugs based on the above-mentioned basis.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48910207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-12DOI: 10.3390/biophysica3030032
G. Menezes, M. Saivish, L. Sacchetto, G. C. D. da Silva, Igor da Silva Teixeira, Natalia Franco Bueno Mistrão, M. Nogueira, J. I. N. Oliveira, K. S. Bezerra, R. D. da Silva, U. L. Fulco
The Oropouche virus is an orthobunyavirus responsible for causing Oropouche fever, a disease that primarily affects thousands of people in South and Central America. Currently, no specific antiviral treatments or vaccines are available against this virus, highlighting the urgent need for safe, affordable, and effective therapies. Natural products serve as an important source of bioactive compounds, and there is growing interest in identifying natural bioactive molecules that could be used for treating viral diseases. Quercetin hydrate is a compound classified as a flavonoid, which has garnered scientific attention due to its potential health benefits and its presence in various plant-based foods. In this study, we aim to evaluate the in vitro antiviral activity of quercetin hydrate against the Oropouche virus (OROV). Furthermore, we intend to explore its mode of action through in silico approaches. The cytotoxicity and antiviral activity of the compound were assessed using Vero cells. In addition, in silico studies were also performed through molecular docking, molecular dynamics simulations, Molecular Mechanics Poisson–Boltzmann surface area (MM/PBSA), and quantum-mechanical analysis in order to evaluate the interaction with the Gc protein of OROV. The assay revealed that the compound was highly active against the virus, inhibiting OROV with an EC50 value of 53.5 ± 26.5 µM under post-infection treatment conditions. The present study demonstrates that the compound is a promising antiviral agent; however, the mechanisms of action proposed in this study need to be experimentally verified by future assays.
{"title":"Exploring Quercetin Hydrate’s Potential as an Antiviral Treatment for Oropouche Virus","authors":"G. Menezes, M. Saivish, L. Sacchetto, G. C. D. da Silva, Igor da Silva Teixeira, Natalia Franco Bueno Mistrão, M. Nogueira, J. I. N. Oliveira, K. S. Bezerra, R. D. da Silva, U. L. Fulco","doi":"10.3390/biophysica3030032","DOIUrl":"https://doi.org/10.3390/biophysica3030032","url":null,"abstract":"The Oropouche virus is an orthobunyavirus responsible for causing Oropouche fever, a disease that primarily affects thousands of people in South and Central America. Currently, no specific antiviral treatments or vaccines are available against this virus, highlighting the urgent need for safe, affordable, and effective therapies. Natural products serve as an important source of bioactive compounds, and there is growing interest in identifying natural bioactive molecules that could be used for treating viral diseases. Quercetin hydrate is a compound classified as a flavonoid, which has garnered scientific attention due to its potential health benefits and its presence in various plant-based foods. In this study, we aim to evaluate the in vitro antiviral activity of quercetin hydrate against the Oropouche virus (OROV). Furthermore, we intend to explore its mode of action through in silico approaches. The cytotoxicity and antiviral activity of the compound were assessed using Vero cells. In addition, in silico studies were also performed through molecular docking, molecular dynamics simulations, Molecular Mechanics Poisson–Boltzmann surface area (MM/PBSA), and quantum-mechanical analysis in order to evaluate the interaction with the Gc protein of OROV. The assay revealed that the compound was highly active against the virus, inhibiting OROV with an EC50 value of 53.5 ± 26.5 µM under post-infection treatment conditions. The present study demonstrates that the compound is a promising antiviral agent; however, the mechanisms of action proposed in this study need to be experimentally verified by future assays.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44810145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-26DOI: 10.3390/biophysica3030031
Xiaolin Zhou, Yifan Qin
We studied the dynamic behavior of a single semiflexible ring in linear chain matrix based on a coarse-grained model using the molecular dynamics simulation approach. We found that that ring chains’ hollow centers are frequently filled with linear chains. However, as the rigidity of the linear chains increases, the linear chains arranged parallel to each other and the ring chain are temporary caged. As a result, the swing movement in the normal direction of the ring is significantly limited, and the relaxation time in the normal direction increases significantly. Our findings can help to understand the physical mechanism of the movement of the ring chain in ring–linear polymer blends at the microscopic level.
{"title":"The Dynamic Behavior of a Single Semiflexible Ring Chain in a Linear Polymer Matrix","authors":"Xiaolin Zhou, Yifan Qin","doi":"10.3390/biophysica3030031","DOIUrl":"https://doi.org/10.3390/biophysica3030031","url":null,"abstract":"We studied the dynamic behavior of a single semiflexible ring in linear chain matrix based on a coarse-grained model using the molecular dynamics simulation approach. We found that that ring chains’ hollow centers are frequently filled with linear chains. However, as the rigidity of the linear chains increases, the linear chains arranged parallel to each other and the ring chain are temporary caged. As a result, the swing movement in the normal direction of the ring is significantly limited, and the relaxation time in the normal direction increases significantly. Our findings can help to understand the physical mechanism of the movement of the ring chain in ring–linear polymer blends at the microscopic level.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43875481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-21DOI: 10.3390/biophysica3030030
P. Ojeda-May
Understanding the connection between local and global dynamics can provide valuable insights into enzymatic function and may contribute to the development of novel strategies for enzyme modulation. In this work, we investigated the dynamics at both the global and local (active site) levels of Shikimate Kinase (SK) through microsecond time-scale molecular dynamics (MD) simulations of the holoenzyme in the product state. Our focus was on the wild-type (WT) enzyme and two mutants (R116A and R116K) which are known for their reduced catalytic activity. Through exploring the dynamics of these variants, we gained insights into the role of residue R116 and its contribution to overall SK dynamics. We argue that the connection between local and global dynamics can be attributed to local frustration near the mutated residue which perturbs the global protein dynamics.
{"title":"Exploring the Dynamics of Holo-Shikimate Kinase through Molecular Mechanics","authors":"P. Ojeda-May","doi":"10.3390/biophysica3030030","DOIUrl":"https://doi.org/10.3390/biophysica3030030","url":null,"abstract":"Understanding the connection between local and global dynamics can provide valuable insights into enzymatic function and may contribute to the development of novel strategies for enzyme modulation. In this work, we investigated the dynamics at both the global and local (active site) levels of Shikimate Kinase (SK) through microsecond time-scale molecular dynamics (MD) simulations of the holoenzyme in the product state. Our focus was on the wild-type (WT) enzyme and two mutants (R116A and R116K) which are known for their reduced catalytic activity. Through exploring the dynamics of these variants, we gained insights into the role of residue R116 and its contribution to overall SK dynamics. We argue that the connection between local and global dynamics can be attributed to local frustration near the mutated residue which perturbs the global protein dynamics.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42081932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-07DOI: 10.3390/biophysica3030029
Ingrid V. Machado, Luiz F. N. Naves, Jean M. F. Custódio, H. D. A. Vidal, J. E. Queiroz, A. Oliver, Joyce V. B. Borba, B. J. Neves, L. M. Brito, C. Pessoa, H. Napolitano, G. Aquino
Cancer resistance to chemotherapy and radiation therapies presents significant challenges, necessitating the exploration of alternative approaches. Targeting specific proteins at the molecular level, particularly their active sites, holds promise in addressing this issue. We investigated the potential of 4′-methoxy-2-nitrochalcone (MNC) as an MCL-1 inhibitor, examining its chemical and structural characteristics to elucidate its biological activity and guide the selection of potential candidates. We conducted a docking study, followed by synthesis, structural characterization, theoretical calculations, and in vitro experiments to comprehensively evaluate MNC. The docking results revealed MNC’s excellent binding within the active site of MCL-1. At 50 µM, MNC demonstrated 99% inhibition of HCT116 cell proliferation, with an IC50 value of 15.18 µM after 24 h. Treatment with MNC at 30.36 and 15.18 µM resulted in reduced cell density. Notably, MNC exhibited marked cytotoxicity at concentrations of 15.58 µM and 7.79 µM, inducing high frequencies of plasma membrane rupture and apoptosis, respectively. Our findings highlight the significant biological potential of MNC as an MCL-1 inhibitor. Furthermore, we propose exploring chalcones with hydrogen bond acceptor substituents as promising candidates for studying inhibitors targeting this protein. In conclusion, our study addresses the challenge of cancer resistance by investigating MNC as an MCL-1 inhibitor. Through detailed characterization and experimental validation, we establish the efficacof MNC in inhibiting cell proliferation and inducing cytotoxic effects. These results underscore the potential of MNC as a valuable therapeutic agent and suggest the use of chalcones with hydrogen bond acceptor substituents as a basis for developing novel MCL-1 inhibitors.
{"title":"A Structure-Guided Designed Small Molecule Is an Anticancer Agent and Inhibits the Apoptosis-Related MCL-1 Protein","authors":"Ingrid V. Machado, Luiz F. N. Naves, Jean M. F. Custódio, H. D. A. Vidal, J. E. Queiroz, A. Oliver, Joyce V. B. Borba, B. J. Neves, L. M. Brito, C. Pessoa, H. Napolitano, G. Aquino","doi":"10.3390/biophysica3030029","DOIUrl":"https://doi.org/10.3390/biophysica3030029","url":null,"abstract":"Cancer resistance to chemotherapy and radiation therapies presents significant challenges, necessitating the exploration of alternative approaches. Targeting specific proteins at the molecular level, particularly their active sites, holds promise in addressing this issue. We investigated the potential of 4′-methoxy-2-nitrochalcone (MNC) as an MCL-1 inhibitor, examining its chemical and structural characteristics to elucidate its biological activity and guide the selection of potential candidates. We conducted a docking study, followed by synthesis, structural characterization, theoretical calculations, and in vitro experiments to comprehensively evaluate MNC. The docking results revealed MNC’s excellent binding within the active site of MCL-1. At 50 µM, MNC demonstrated 99% inhibition of HCT116 cell proliferation, with an IC50 value of 15.18 µM after 24 h. Treatment with MNC at 30.36 and 15.18 µM resulted in reduced cell density. Notably, MNC exhibited marked cytotoxicity at concentrations of 15.58 µM and 7.79 µM, inducing high frequencies of plasma membrane rupture and apoptosis, respectively. Our findings highlight the significant biological potential of MNC as an MCL-1 inhibitor. Furthermore, we propose exploring chalcones with hydrogen bond acceptor substituents as promising candidates for studying inhibitors targeting this protein. In conclusion, our study addresses the challenge of cancer resistance by investigating MNC as an MCL-1 inhibitor. Through detailed characterization and experimental validation, we establish the efficacof MNC in inhibiting cell proliferation and inducing cytotoxic effects. These results underscore the potential of MNC as a valuable therapeutic agent and suggest the use of chalcones with hydrogen bond acceptor substituents as a basis for developing novel MCL-1 inhibitors.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49073564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-28DOI: 10.3390/biophysica3030028
P. Alves, Gagan Preet, M. Oliveira, L. Dias, Giovanna B Silva, Maria Luísa Lima Barreto do Nascimento, A. Reis, João Marcelo Sousa, J. Júnior, N. Lima, T. Andrade, C. Feitosa
In this study, secondary metabolites, toxicology and antioxidant properties of chloroform fractions from leaves (FCFMh), branches (FCGMh), and roots (FCRMh) of Mansoa hirsuta were investigated. The phytochemical screening detected flavonoids, especially chalcones. Through Liquid chromatography with mass spectrometry—LC–MS analysis, the flavonoids (isoorientin-2″-O-arabinoside), triterpenes (oleanolic acid and ursolic acid) and ceramide (phytosphingosine) were identified. From the Artemia salina assay, the fraction FCGMh was the most toxic (LC50 = 64.21 µg·mL−1), followed by FCRMh (LC50 = 87.61 µg·mL−1) and FCFMh (LC50 = 421.9 µg·mL−1). Concerning the cytotoxic potential, the root fraction (IC50 16.48 μg mL−1) displayed the highest cytotoxicity against the breast cancer cell line (4T1), followed by leaves (IC50 33.13 μg mL−1) and branches (IC50 of 47.13 μg mL−1). In conclusion, all the fractions of M. hirsuta showed cytotoxicity at the highest concentrations; however, remarkable biological properties were found for the root fractions. Computational analysis was performed using a molecular docking and pharmacophore approach to understand the antioxidant activity of its major metabolites.
{"title":"Screening for Bioactive Metabolites in Leaves, Branches, and Roots of Mansoa hirsuta: Phytochemical, Toxicological and Antioxidant Aspects","authors":"P. Alves, Gagan Preet, M. Oliveira, L. Dias, Giovanna B Silva, Maria Luísa Lima Barreto do Nascimento, A. Reis, João Marcelo Sousa, J. Júnior, N. Lima, T. Andrade, C. Feitosa","doi":"10.3390/biophysica3030028","DOIUrl":"https://doi.org/10.3390/biophysica3030028","url":null,"abstract":"In this study, secondary metabolites, toxicology and antioxidant properties of chloroform fractions from leaves (FCFMh), branches (FCGMh), and roots (FCRMh) of Mansoa hirsuta were investigated. The phytochemical screening detected flavonoids, especially chalcones. Through Liquid chromatography with mass spectrometry—LC–MS analysis, the flavonoids (isoorientin-2″-O-arabinoside), triterpenes (oleanolic acid and ursolic acid) and ceramide (phytosphingosine) were identified. From the Artemia salina assay, the fraction FCGMh was the most toxic (LC50 = 64.21 µg·mL−1), followed by FCRMh (LC50 = 87.61 µg·mL−1) and FCFMh (LC50 = 421.9 µg·mL−1). Concerning the cytotoxic potential, the root fraction (IC50 16.48 μg mL−1) displayed the highest cytotoxicity against the breast cancer cell line (4T1), followed by leaves (IC50 33.13 μg mL−1) and branches (IC50 of 47.13 μg mL−1). In conclusion, all the fractions of M. hirsuta showed cytotoxicity at the highest concentrations; however, remarkable biological properties were found for the root fractions. Computational analysis was performed using a molecular docking and pharmacophore approach to understand the antioxidant activity of its major metabolites.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48590221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-23DOI: 10.3390/biophysica3030027
Viswanath Vittaladevaram, D. Cheung
Fibronectin is a multi-domain, extracellular matrix protein that plays a number of biological roles. As the adsorption of fibronectin onto the surface of implanted devices can lead to an inflammatory response or bacterial colonisation, understanding the interaction of fibronectin with material surfaces is important in the design of materials for biomedical applications. This, however, relies on having knowledge of the molecular-scale behaviour of proteins, which is difficult to investigate experimentally. In this paper, we used molecular dynamics simulations to investigate the adsorption of heparin-binding fibronectin domains onto hydrophobic surfaces. Despite the high similarity between these, their adsorption differs both in terms of the strength and the specificity of this, indicating that relatively small changes in protein structure can lead to significant changes in adsorption behaviour. This suggests that the interplay between protein structure and surface chemistry is vital for understanding the protein adsorption process and the design of novel biomaterials.
{"title":"Adsorption of Heparin-Binding Fragments of Fibronectin onto Hydrophobic Surfaces","authors":"Viswanath Vittaladevaram, D. Cheung","doi":"10.3390/biophysica3030027","DOIUrl":"https://doi.org/10.3390/biophysica3030027","url":null,"abstract":"Fibronectin is a multi-domain, extracellular matrix protein that plays a number of biological roles. As the adsorption of fibronectin onto the surface of implanted devices can lead to an inflammatory response or bacterial colonisation, understanding the interaction of fibronectin with material surfaces is important in the design of materials for biomedical applications. This, however, relies on having knowledge of the molecular-scale behaviour of proteins, which is difficult to investigate experimentally. In this paper, we used molecular dynamics simulations to investigate the adsorption of heparin-binding fibronectin domains onto hydrophobic surfaces. Despite the high similarity between these, their adsorption differs both in terms of the strength and the specificity of this, indicating that relatively small changes in protein structure can lead to significant changes in adsorption behaviour. This suggests that the interplay between protein structure and surface chemistry is vital for understanding the protein adsorption process and the design of novel biomaterials.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46837924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-15DOI: 10.3390/biophysica3020026
Rodward L. Hewlin, Maegan Edwards, J. Kizito
This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug.
{"title":"A Two-Species Finite Volume Scalar Model for Modeling the Diffusion of Poly(lactic-co-glycolic acid) into a Coronary Arterial Wall from a Single Half-Embedded Drug Eluting Stent Strut","authors":"Rodward L. Hewlin, Maegan Edwards, J. Kizito","doi":"10.3390/biophysica3020026","DOIUrl":"https://doi.org/10.3390/biophysica3020026","url":null,"abstract":"This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46356152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-31DOI: 10.3390/biophysica3020025
I. Polyakov, A. Nemukhin
We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed using coordinates of heavy atoms from the crystal structure PDB ID 6OB2 with the GTP analog GMPPNP. Large-scale classical molecular dynamics (MD) calculations were performed to analyze conformations of the enzyme-substrate complexes. The Gibbs energy profiles for the hydrolysis reaction were computed using MD simulations with quantum mechanics/molecular mechanics (QM/MM) interaction potentials. The density functional theory DFT(ωB97X-D3/6-31G**) approach was applied in QM and the CHARMM36 force field parameters in MM. The most likely scenario of the chemical step of the GTP hydrolysis in KRas-NF1 corresponds to the water-assisted mechanism of the formation of the inorganic phosphate coupled with the dissociation of GTP to GDP.
我们报告了KRas-NF1蛋白复合物活性位点鸟苷三磷酸(GTP)水解的计算研究结果，其中KRas代表Ras (Ras肉瘤)蛋白的k -异构体，NF1(神经纤维蛋白-1)是激活蛋白。用GTP类似物GMPPNP的晶体结构PDB ID 6OB2的重原子坐标来构建模型系统。采用大规模经典分子动力学(MD)计算分析酶-底物复合物的构象。利用量子力学/分子力学(QM/MM)相互作用势进行动力学模拟，计算了水解反应的吉布斯能谱。在QM中采用密度泛函理论DFT(ωB97X-D3/6-31G**)方法，在MM中采用CHARMM36力场参数。在KRas-NF1中，GTP水解的化学步骤最可能的情景对应于无机磷酸盐的形成和GTP解离成GDP的水辅助机制。
{"title":"Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein","authors":"I. Polyakov, A. Nemukhin","doi":"10.3390/biophysica3020025","DOIUrl":"https://doi.org/10.3390/biophysica3020025","url":null,"abstract":"We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed using coordinates of heavy atoms from the crystal structure PDB ID 6OB2 with the GTP analog GMPPNP. Large-scale classical molecular dynamics (MD) calculations were performed to analyze conformations of the enzyme-substrate complexes. The Gibbs energy profiles for the hydrolysis reaction were computed using MD simulations with quantum mechanics/molecular mechanics (QM/MM) interaction potentials. The density functional theory DFT(ωB97X-D3/6-31G**) approach was applied in QM and the CHARMM36 force field parameters in MM. The most likely scenario of the chemical step of the GTP hydrolysis in KRas-NF1 corresponds to the water-assisted mechanism of the formation of the inorganic phosphate coupled with the dissociation of GTP to GDP.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46966867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-24DOI: 10.3390/biophysica3020024
Nikita N. Ivanov, D. Shulga, V. Palyulin
In the drug design process, a frequent task is the decomposition of small molecules into fragments. There exist a number of approaches and methods to break molecules into fragments. However, a method that allows the decomposition of molecules into non-overlapping fragments that is meaningful in terms of medicinal chemistry is absent, and in this work, we present a new simple approach for the decomposition of molecules—MedChemFrag. It aims to break drug-like molecules into a set of rings and linkers, which are close to the perception of “fragments” by medicinal chemists. In contrast to most previous efforts aimed at breaking molecules using retrosynthetic feasible rules, our approach strives to preserve the functional groups, which may reveal the specific interaction pattern, e.g., the amide groups.
{"title":"Decomposition of Small Molecules for Fragment-Based Drug Design","authors":"Nikita N. Ivanov, D. Shulga, V. Palyulin","doi":"10.3390/biophysica3020024","DOIUrl":"https://doi.org/10.3390/biophysica3020024","url":null,"abstract":"In the drug design process, a frequent task is the decomposition of small molecules into fragments. There exist a number of approaches and methods to break molecules into fragments. However, a method that allows the decomposition of molecules into non-overlapping fragments that is meaningful in terms of medicinal chemistry is absent, and in this work, we present a new simple approach for the decomposition of molecules—MedChemFrag. It aims to break drug-like molecules into a set of rings and linkers, which are close to the perception of “fragments” by medicinal chemists. In contrast to most previous efforts aimed at breaking molecules using retrosynthetic feasible rules, our approach strives to preserve the functional groups, which may reveal the specific interaction pattern, e.g., the amide groups.","PeriodicalId":72401,"journal":{"name":"Biophysica","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48803246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：