Identifying the Interaction of Vancomycin With Novel pH-Responsive Lipids as Antibacterial Biomaterials Via Accelerated Molecular Dynamics and Binding Free Energy Calculations.

Nano-drug delivery systems have proven to be an efficient formulation tool to overcome the challenges with current antibiotics therapy and resistance. A series of pH-responsive lipid molecules were designed and synthesized for future liposomal formulation as a nano-drug delivery system for vancomycin at the infection site. The structures of these lipids differ from each other in respect of hydrocarbon tails: Lipid1, 2, 3 and 4 have stearic, oleic, linoleic, and linolenic acid hydrocarbon chains, respectively. The impact of variation in the hydrocarbon chain in the lipid structure on drug encapsulation and release profile, as well as mode of drug interaction, was investigated using molecular modeling analyses. A wide range of computational tools, including accelerated molecular dynamics, normal molecular dynamics, binding free energy calculations and principle component analysis, were applied to provide comprehensive insight into the interaction landscape between vancomycin and the designed lipid molecules. Interestingly, both MM-GBSA and MM-PBSA binding affinity calculations using normal molecular dynamics and accelerated molecular dynamics trajectories showed a very consistent trend, where the order of binding affinity towards vancomycin was lipid4 > lipid1 > lipid2 > lipid3. From both normal molecular dynamics and accelerated molecular dynamics, the interaction of lipid3 with vancomycin is demonstrated to be the weakest (∆Gbinding = -2.17 and -11.57, for normal molecular dynamics and accelerated molecular dynamics, respectively) when compared to other complexes. We believe that the degree of unsaturation of the hydrocarbon chain in the lipid molecules may impact on the overall conformational behavior, interaction mode and encapsulation (wrapping) of the lipid molecules around the vancomycin molecule. This thorough computational analysis prior to the experimental investigation is a valuable approach to guide for predicting the encapsulation ability, drug release and further development of novel liposome-based pH-responsive nano-drug delivery system with refined structural and chemical features of potential lipid molecule for formulation development.

An unexplored remarkable PNIPAM-osmolyte interaction study: An integrated experimental and simulation approach.

We investigate the aggregation and collapse of water soluble amphiphilic polymer, poly(N-isopropylacrylamide) (PNIPAM), in aqueous solution containing variable amount of trehalose, sucrose and sorbitol. The effect of these osmolytes on the coil to globular transition of the PNIPAM is studied by the use of comprehensive biophysical techniques like UV-visible spectroscopy, fluorescence spectroscopy, dynamic light scattering and Fourier transform infrared spectroscopy (FTIR). The polarization induced by these additives promotes the collapsed state of PNIPAM at much lower temperature as compared to the pure PNIPAM in aqueous solution. The decrease in the lower critical solution temperature (LCST) of the polymer with increase in the concentration of osmolyte is due to the significant changes in the interactions among polymer, osmolyte and water. The high affinity of these additives toward water destabilize the hydrated macromolecular structure via preferential interactions. To investigate the molecular mechanism behind the decrease in the LCST of the polymer in presence of the osmolytes, a molecular dynamics (MD) study was performed. The MD simulation has clearly shown the reduction in hydration shell of the polymer after interacting with the osmolyte. MD study revealed significant changes in polymer conformation because of osmolyte interaction and strongly supports the experimental observation of polymer phase transition at temperature lower than typical LCST. The driving force for concomitant sharp configurational transition has been attributed to the rupture of hydrogen bonds between water and polymer and to the hydrophobic association of the polymer. The results of the present study can be used in the bioresponsive smart PNIPAM-based devices as its LCST is close to body temperature. This study provides an alternative method to tune the LCST of the widely accepted model PNIPAM polymer.

Comprehensive Computational and Experimental Analysis of Biomaterial toward the Behavior of Imidazolium-Based Ionic Liquids: An Interplay between Hydrophilic and Hydrophobic Interactions.

To provide insights into the aggregation behavior, hydration tendency and variation in phase transition temperature produced by the addition of ionic liquids (ILs) to poly(N-isopropylacrylamide) (PNIPAM) aqueous solution, systematic physicochemical studies, and molecular dynamic simulations were carried out. The influence of ILs possessing the same [Cl]- anion and a set of cations [Cnmim]+ with increasing alkyl chain length such as 1-ethyl-3-methylimidazolium ([Emim]+), 1-allyl-3-methylimidazolium ([Amim]+), 1-butyl-3-methylimidazolium ([Bmim]+), 1-hexyl-3-methylimidazolium ([Hmim]+), 1-benzyl-3-methylimidazolium ([Bzmim]+), and 1-decyl-3-methylimidazolium ([Dmim]+) on the phase transition of PNIPAM was monitored by the aid of UV-visible absorption spectra, fluorescence intensity spectra, viscosity (η), dynamic light scattering (DLS), and Fourier transform infrared (FTIR) spectroscopy. Furthermore, to interpret the direct images and surface morphologies of the PNIPAM-IL aggregates, we performed field emission scanning electron microscopy (FESEM). The overall specific ranking of ILs in preserving the hydration layer around the PNIPAM aqueous solution was [Emim][Cl] > [Amim][Cl] > [Bmim][Cl] > [Hmim][Cl] > [Bzmim][Cl] > [Dmim][Cl]. Moreover, to investigate the molecular mechanism behind the change in the lower critical solution temperature (LCST) of the polymer in the presence of the ILs, a molecular dynamics (MD) study was performed. The MD simulation has clearly shown the reduction in hydration shell of the polymer after interacting with the ILs at their respective LCST. MD study revealed significant changes in polymer conformation because of IL interactions and strongly supports the experimental observation of polymer phase transition at a temperature lower than typical LCST for all the studied ILs. The driving force for concomitant sharp configurational transition has been attributed to the displacement of water molecules on the polymer surface by the ILs because of their hydrophobic interaction with the polymer.

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

Ultra-small lipid-dendrimer hybrid nanoparticles as a promising strategy for antibiotic delivery: In vitro and in silico studies.

The purpose of this study was to explore the preparation of a new lipid-dendrimer hybrid nanoparticle (LDHN) system to effectively deliver vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) infections. Spherical LDHNs with particle size, polydispersity index and zeta potential of 52.21±0.22 nm, 0.105±0.01, and -14.2±1.49 mV respectively were prepared by hot stirring and ultrasonication using Compritol 888 ATO, G4 PAMAM- succinamic acid dendrimer, and Kolliphor RH-40. Vancomycin encapsulation efficiency (%) in LDHNs was almost 4.5-fold greater than in lipid-polymer hybrid nanoparticles formulated using Eudragit RS 100. Differential scanning calorimetry and Fourier transform-infrared studies confirmed the formation of LDHNs. The interactions between the drug-dendrimer complex and lipid molecules using in silico modeling revealed the molecular mechanism behind the enhanced encapsulation and stability. Vancomycin was released from LDHNs over the period of 72 h with zero order kinetics and super case II transport mechanism. The minimum inhibitory concentration (MIC) against S. aureus and MRSA were 15.62 µg/ml and 7.81 µg/ml respectively. Formulation showed sustained activity with MIC of 62.5 µg/ml against S. aureus and 500 µg/ml against MRSA at the end of 72 and 54 h period respectively. The results suggest that the LDHN system can be an effective strategy to combat resistant infections.

In Silico Characterization of the Binding Affinity of Dendrimers to Penicillin-Binding Proteins (PBPs): Can PBPs be Potential Targets for Antibacterial Dendrimers?

We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a Diverse Therapeutic Target: A Computational Perspective.

Adenosine monophosphate-activated protein kinase (AMPK) is viewed as a privileged therapeutic target for several diseases such as cancer, diabetes, inflammation, obesity, etc. In addition, AMPK has entered the limelight of current drug discovery with its evolution as a key metabolic regulator. AMPK also plays a key role in the maintenance of cellular energy homeostasis. Structurally, AMPK is a heterotrimeric protein, which consists of three protein subunits (α, ß, and γ). The crystal structure of AMPK was solved, and several computational studies including homology modeling, molecular docking, molecular dynamics, and QSAR have been reported in order to explore the structure and function of this diverse therapeutic target. In this review, we present a comprehensive up-to-date overview on the computational and molecular modeling approaches that have been carried out on AMPK in order to understand its structure, function, dynamics, and its drug binding landscape. Information provided in this review would be of great interest to a wide pool of researchers involved in the design of new molecules against various diseases where AMPK plays a predominant role.

(2E)-1-(5-Bromothiophen-2-yl)-3-(4-chloro-phen-yl)prop-2-en-1-one.

In the title compound, C13H8BrClOS, the thio-phene and phenyl rings are inclined by 40.69 (11)° to each other. The crystal structure is characterized by C-H⋯π inter-actions, which link the mol-ecules into broad layers parallel to (100). Short Br⋯Cl contacts [3.698 (1) Å] link these layers along [100].

(2E)-3-(2-Bromo-phen-yl)-1-(5-bromo-thio-phen-2-yl)prop-2-en-1-one.

The asymmetric unit of the title compound, C13H8Br2OS, contains two mol-ecules, in which the dihedral angles between the thio-phene and benzene rings are 10.5 (3) and 33.2 (4)°. There are no significant directional inter-actions in the crystal.

(E)-1-(5-Bromo-thio-phen-2-yl)-3-(3,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one.

In the title compound, C(16)H(15)BrO(4)S, the dihedral angle between the thio-phene and benzene rings is 13.08 (16)°. The C atoms of the meta meth-oxy groups of the substituted benzene ring lie close to the plane of the ring [displacements = 0.049 (5) and -0.022 (4) Å], whereas the para-C atom is significantly displaced [-1.052 (4) Å]. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming C(11) chains propagating in [100].