1,721,030 research outputs found
Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair
Full text linkGENERATION 2 CATIONIC CARBOSILANE DENDRIMERS HOLD GREAT PROMISE AS INTERNALIZING AGENTS FOR GENE THERAPY AS THEY PRESENT LOW TOXICITY AND RETAIN AND INTERNALIZE GENETIC MATERIAL AS OLIGONUCLEOTIDE OR SIRNA. IN THIS WORK WE CARRIED OUT A COMPLETE IN SILICO STRUCTURAL AND ENERGETICAL CHARACTERIZATION OF THE INTERACTIONS OF A SET OF 2G CARBOSILANE DENDRIMERS, SHOWING DIFFERENT AFFINITY TOWARDS TWO SINGLE STRAND OLIGONUCLEOTIDE (ODN) SEQUENCES IN VITRO. OUR SIMULATIONS PREDICT THAT THESE FOUR DENDRIMERS AND THE RELEVANT ODN COMPLEXES ARE CHARACTERIZED BY SIMILAR SIZE AND SHAPE, AND THAT THE MOLECULE-SPECIFIC ODN BINDING ABILITY CAN BE RATIONALIZED ONLY CONSIDERING A CRITICAL MOLECULAR DESIGN PARAMETER: THE NORMALIZED EFFECTIVE BINDING ENERGY ΔGBIND,EFF/NEFF I.E., THE PERFORMANCE OF EACH ACTIVE INDIVIDUAL DENDRIMER BRANCH DIRECTLY INVOLVED IN A BINDING INTERACTIO
Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence
Full text linkThe coronavirus disease-2019 (COVID-19) pandemic, caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China during late 2019 and swiftly spread worldwide. Since COVID-19 emergence, many therapeutic regimens have been relentlessly explored, and although two vaccines have just received emergency use authorization by different governmental agencies, antiviral therapeutics based neutralizing antibodies and small-drug inhibitors can still be vital viable options to prevent and treat SARS-CoV-2 infections. The viral spike glycoprotein (S-protein) is the key molecular player that promotes human host cellular invasion via recognition of and binding to the angiotensin-converting enzyme 2 gene (ACE2). In this work, we report the results obtained by mutating in silico the 18 ACE2 residues and the 14 S-protein receptor binding domain (S-RBDCoV-2) residues that contribute to the receptor/viral protein binding interface. Specifically, each wild-type protein-protein interface residue was replaced by a hydrophobic (isoleucine), polar (serine and threonine), charged (aspartic acid/glutamic acid and lysine/arginine), and bulky (tryptophan) residue, respectively, in order to study the different effects exerted by nature, shape, and dimensions of the mutant amino acids on the structure and strength of the resulting binding interface. The computational results were next validated a posteriori against the corresponding experimental data, yielding an overall agreement of 92%. Interestingly, a non-negligible number of mis-sense variations were predicted to enhance ACE2/S-RBDCoV-2 binding, including the variants Q24T, T27D/K/W, D30E, H34S7T/K, E35D, Q42K, L79I/W, R357K, and R393K on ACE2 and L455D/W, F456K/W, Q493K, N501T, and Y505W on S-RBDCoV-2, respectively
Structure and binding thermodynamics of viologen-phosphorous dendrimers to human serum albumin: A combined computational/experimental investigation
No full textLow-generation viologen-phosphorous dendrimers (VPDs) can be exploited as novel therapeutic agents, since they efficiently inhibit aggregation of amyloid-β into fibrils and are active against several strains of microorganisms. Human serum albumin (HSA), the most abundant plasma protein, is playing an increasing role as drug carrier in the clinical setting. Therefore, with the aim of exploiting HSA as a potential carrier for VPDs, in this work we performed a preliminary investigation of the interaction of six different VPDs 1–6 with HSA using a combined computational/experimental approach. First, different modeling techniques were employed to i) determine the dendrimer binding site on the HSA surface; ii) derive the free energy change ΔGb involved in each dendrimer/HSA complex formation; iii) analyze in details all molecular determinants contributing to ΔGb, and iv) evaluate the eventual HSA structural variations induced by dendrimer binding. All modeling predictions were next validated using a series of experimental techniques, including isothermal titration calorimetry (ITC), circular dichroism (CD), and fluorescence quenching and decay. In aggregate, the results from this study allowed us to rank the affinity of the different viologen-phosphorous dendrimers 1–6 towards HSA and to formulate a molecular-based rationale for the differential binding thermodynamics of the resulting dendrimer/HSA complexes. According to our data, HSA can successfully and selectively bind VPDs 1–6, dendrimer 4 being the best cargo for this endogenous protein nanocarrier
Molecular Interactions of Cobimetinib and Vemurafenib with Human Serum Albumin: a Comparative Biophysical and Computational Analysis
No full textThe combined use of BRAF and MEK inhibitors has transformed the management of BRAFV600-mutated melanoma, yet the pharmacokinetic interplay between cobimetinib (COB) and vemurafenib (VEM) remains incompletely understood. Here, we investigated the binding interactions of COB and VEM with human serum albumin (HSA) using a multidisciplinary approach combining fluorescence spectroscopy, isothermal titration calorimetry, circular dichroism, and molecular simulations. Both inhibitors form stable complexes with HSA, predominantly at Sudlow’s site II, driven by different interactions pattern. Thermodynamic and kinetic analyses revealed distinct binding behaviors: COB binding is entropy-driven (ΔH = +5.88 ± 0.32 kJ/mol; ΔG = −24.19 kJ/mol), with a dissociation constant (Kd) of 58.2 μM and a residence time of 1.45 s, indicating rapid and dynamic engagement. In contrast, VEM displays a more enthalpy-favored profile (ΔH = −22.05 ± 0.31 kJ/mol), stronger binding affinity (Kd≈ 4.8 μM), and a longer residence time of 18.5 s. Stoichiometry for both ligands is approximately 1:1, as determined by ITC. Structural analyses revealed subtle conformational alterations in HSA upon ligand binding, while enzymatic assays demonstrated that both COB and VEM competitively inhibit HSA’s esterase-like activity. These findings highlight distinct binding kinetics and functional consequences for each drug, offering critical insights into their pharmacokinetic behavior during combination therapy and providing a foundation for optimizing systemic exposure and therapeutic efficacy
In silico design of self-assembly nanostructured polymer systems by multiscale molecular modeling
Full text linkThe fast development of digitalization and computational science is opening new possibilities
for a rapid design of new materials. Computational tools coupled with focused experiments can
be successfully used for the design of new nanostructured materials in different sectors, particularly
in the area of biomedical applications. This paper starts with a general introduction on
the future of computational tools for the design of new materials and introduces the paradigm
of multiscale molecular modeling. It then continues with the description of the multiscale (i.e.,
atomistic, mesoscale and finite element calculations) computational recipe for the prediction of
novel materials and structures for biomedical applications. Finally, the comparison of in silico
and experimental results on selected systems of interest in the area of life sciences is reported
and discussed. The quality of the agreement obtained between virtual and real data for such
complex systems indeed confirms the validity of computational tools for the design of nanostructured
polymer systems for biomedical applications
Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study
Full text link: Drug binding to human serum albumin (HSA) significantly affects in vivo drug transport and biological activity. To gain insight into the binding mechanism of the two B-Raf tyrosine kinase inhibitors dabrafenib and vemurafenib to HSA, in this work, we adopted a combined strategy based on fluorescence spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD), and molecular simulations. Both anticancer drugs are found to bind spontaneously and with a 1:1 stoichiometry within the same binding pocket, located in Sudlow's site II (subdomain IIIA) of the protein with comparable affinity and without substantially perturbing the protein secondary structure. However, the nature of each drug-protein interactions is distinct: whereas the formation of the dabrafenib/HSA complex is more entropically driven, the formation of the alternative vemurafenib/HSA assembly is prevalently enthalpic in nature. Kinetic analysis also indicates that the association rate is similar for the two drugs, whereas the residence time of vemurafenib within the HSA binding pocket is somewhat higher than that determined for the alternative B-Raf inhibitor
Targeted drug delivery: concepts, approaches, and applications
No full textTargeted drug delivery (TDD) is a relatively novel approach that aims at delivering a drug to a specific site of action or absorption while not releasing it elsewhere in the body. TDD systems provide several benefits over traditional drug administration methods, including greater pharmacological activity, less side effects, and reduced therapeutic regimens. The delivery system is intended to maintain the drug in its original form until the target spot is reached and the cargo is released in situ. The “magic bullet” concept was designed to attain this goal, and, for more than a century, it has fueled scientific research, resulting in the development of many delivery strategies. The primary purpose of a TDD is to focus the pharmacological impact the therapeutic agent to diseased organs while leaving healthy tissues undisturbed, which is exceptionally critical in cancer chemotherapeutics. Active and passive targeting, ligand-mediated targeting, inverse targeting, dual targeting, physical targeting, and double targeting are all examples of TDD mechanisms; yet, almost the totality of these processes requires the help of a carrier to accomplish the ultimate goal. These carriers can be divided in three major classes: lipid-, polymeric-, and monoclonal antibody-based drug delivery systems. Each class, in turn, has several subclasses, which will also be presented and discussed in this chapter
Of (computers, cells) mice and men: Integration of simulations and experiments in molecular medicine
No full textMultimodel approach for accurate determination of industry-driven properties for Polymer Nanocomposite Materials
No full textThe need for effective and efficient design and production of sophisticated materials with advancedperformances on a competitive time scale is strongly driving the integration of material modelingand simulation techniques into material selection decision processes. Specifically, for complex struc-tural materials such as polymer-based nanocomposites (PNCs), there is a strong industrial demand forchemistry/physics-based models and modeling workflows able to predict relevant material properties inan accurate and reliable way. Under this perspective, in this work we describe the application of multiscalemolecular modeling techniques for the choice of PNC materials for aerospace applications. The resultsare obtained in the framework of the European project Multi-scale Composite Material Selection Platformwith a Seamless Integration of Materials Models and Multidisciplinary Design Framework (COMPOSELECTOR), funded by the European Commission within the H2020 call Advancing the integration of materialsmodeling in business processes to enhance effective industrial decision making and increase competitiveness
Perceptions and Misconceptions in Molecular Recognition: Key Factors in Self-Assembling Multivalent (SAMul) Ligands/Polyanions Selectivity
Full text linkBiology is dominated by polyanions (cell membranes, nucleic acids, and polysaccharides just to name a few), and achieving selective recognition between biological polyanions and synthetic systems currently constitutes a major challenge in many biomedical applications, nanovectors-assisted gene delivery being a prime example. This review work summarizes some of our recent efforts in this field; in particular, by using a combined experimental/computation approach, we investigated in detail some critical aspects in self-assembled nanomicelles and two major polyanions-DNA and heparin
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