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1.
J Biomol Struct Dyn ; 41(21): 11510-11517, 2023.
Article in English | MEDLINE | ID: mdl-36715129

ABSTRACT

The octanol-water partition coefficient of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) was investigated using atomistic molecular dynamics simulations via thermodynamic integration and multistate Bennett acceptance ratio methods. The GAFF and CHARMM36 force fields were used with six water models widely used in molecular dynamics simulations. The OPC4 water model provided the best agreement with the experimental octanol-water partition coefficient of DPPC using the two force fields. However, there is still plenty of room for improvement in water models with correct estimation of surface tension that uses better and suitable non-bonded interaction parameters between water-water and water-DPPC. The Gibbs free energy of transferring DPPC from octanol to water phase was calculated to be 19.8 ± 0.3 and 20.2 ± 0.3 kcal mol-1, giving a partition coefficient of 14.5 ± 0.4 and 14.8 ± 0.3 for the GAFF and CHARMM36 force fields, respectively. This study reinforces the importance of developing new water models that reproduce experimental surface tensions to reconcile the water-water and water-DPPC non-bonded interactions and the existing discrepancy between experimental measurements of amphiphilic molecules that are important in many areas of scientific applications and industry such as biophysics, surfactant, colloids, membranes, medicine, nanotechnology, and food and pharmaceutical industries, and so on. It raises two important open questions: Is the experimental octanol-water partition coefficient of DPPC reliable? Or is its calculation accurate using the OPC4 water model? With respect to the experimental measurements, there may be non-treated aspects such as the formation of aggregates in aqueous phase and limit of detection of the applied method. And, in the calculation, some effects are not possible to be considered in a correct way or viable time such as calculating quantum effects, sampling all conformations, considering phase transitions, and correctly evaluating the intermolecular forces to estimate an accurate surface tension.Communicated by Ramaswamy H. Sarma.


Subject(s)
Molecular Dynamics Simulation , Water , 1,2-Dipalmitoylphosphatidylcholine , Octanols , Thermodynamics
2.
J Biomol Struct Dyn ; 41(20): 10546-10557, 2023 12.
Article in English | MEDLINE | ID: mdl-36476274

ABSTRACT

The interactions of the antiviral pentapeptide ATN-161 with the closed and open conformations of the α5ß1 integrin, the SARS-CoV-2 major protease, and the omicron variant spike protein complexed with hACE2 were studied using molecular docking and molecular dynamics simulation. Molecular docking was performed to obtain ATN-161 binding poses with these studied protein targets. Subsequently, molecular dynamics simulations were performed to verify the ligand stability at the binding site of each protein target. Pulling simulations, umbrella sampling, and weighted histogram analysis method were used to obtain the potential of mean force of each system and calculate the Gibbs free energy of binding for the ATN-161 peptide in each binding site of these protein targets. The results showed that ATN-161 binds to α5ß1 integrin in its active and inactive form, binds weakly to the omicron variant spike protein complexed with hACE2, and strongly binds to the main protease target.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Molecular Docking Simulation , Spike Glycoprotein, Coronavirus , Peptides , Peptide Hydrolases , Molecular Dynamics Simulation , Antiviral Agents/pharmacology , Integrins , Protease Inhibitors
3.
Proc Natl Acad Sci U S A ; 119(25): e2123564119, 2022 06 21.
Article in English | MEDLINE | ID: mdl-35696565

ABSTRACT

In the context of the rapid increase of antibiotic-resistant infections, in particular of pneumonia, antimicrobial photodynamic therapy (aPDT), the microbiological application of photodynamic therapy (PDT), comes in as a promising treatment alternative since the induced damage and resultant death are not dependent on a specific biomolecule or cellular pathway. The applicability of aPDT using the photosensitizer indocyanine green with infrared light has been successfully demonstrated for different bacterial agents in vitro, and the combination of pulmonary delivery using nebulization and external light activation has been shown to be feasible. However, there has been little progress in obtaining sufficient in vivo efficacy results. This study reports the lung surfactant as a significant suppressor of aPDT in the lungs. In vitro, the clinical surfactant Survanta® reduced the aPDT effect of indocyanine green, Photodithazine®, bacteriochlorin-trizma, and protoporphyrin IX against Streptococcus pneumoniae. The absorbance and fluorescence spectra, as well as the photobleaching profile, suggested that the decrease in efficacy is not a result of singlet oxygen quenching, while a molecular dynamics simulation showed an affinity for the polar head groups of the surfactant phospholipids that likely impacts uptake of the photosensitizers by the bacteria. Methylene blue is the exception, likely because its high water solubility confers a higher mobility when interacting with the surfactant layer. We propose that the interaction between lung surfactant and photosensitizer must be taken into account when developing pulmonary aPDT protocols.


Subject(s)
Anti-Bacterial Agents , Bacteria , Photochemotherapy , Photosensitizing Agents , Surface-Active Agents , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Indocyanine Green/pharmacology , Lung/microbiology , Molecular Dynamics Simulation , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Surface-Active Agents/metabolism
4.
J Chem Inf Model ; 60(12): 5881-5884, 2020 12 28.
Article in English | MEDLINE | ID: mdl-33231448

ABSTRACT

This viewpoint intends to show recent open issues of using coarse grained models in molecular dynamics simulation. It reviews the current knowledge of the comparison between experimental and simulation data of structural and physical chemical properties that depend on the hydrophilic and hydrophobic behavior of the molecule.


Subject(s)
Molecular Dynamics Simulation , Hydrophobic and Hydrophilic Interactions
5.
Biochem Pharmacol ; 164: 64-73, 2019 06.
Article in English | MEDLINE | ID: mdl-30928674

ABSTRACT

As an organ system, the lung has unique advantages and disadvantages for localized drug delivery. Its direct contact with the external environment allows for the upper airways to be easily accessible to intrapulmonary delivery. However, its complex branching structure makes direct delivery to the peripheral airways challenging. This review will discus the utility of exogenous surfactant, a lipoprotein complex currently used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics to enhance the delivery of these drugs to the deeper regions of the lung. The focus is to provide an update on the many tools available to develop new surfactant-based therapeutics using computer modeling, in vitro approaches, and in vivo testing, which may ultimately lead to clinical trials. Two clinical conditions, Acute Respiratory Distress Syndrome and Bacterial Pneumonia are utilized throughout as prototypical examples of pulmonary conditions in which surfactant drug combination may be beneficial. Consequently, the pharmaceuticals discussed are primarily those with antimicrobial or anti-inflammatory activities.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Drug Delivery Systems/methods , Pulmonary Surfactants/administration & dosage , Surface-Active Agents/administration & dosage , Clinical Trials as Topic/methods , Humans , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/metabolism
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