Gibbs Free Energy Of Binding Research Articles

Could Mushrooms' Secondary Metabolites Ameliorate Alzheimer Disease? A Computational Flexible Docking Investigation.

Herein, we highlight the significance of molecular modeling approaches prior to in vitro and invivo studies; particularly, in diseases with no recognized treatments such as neurological abnormalities. Alzheimer disease is a neurodegenerative disorder that causes irreversible cognitive decline. Toxicity and ADMET studies were conducted using the Qikprop platform in Maestro software and Discovery Studio 2.0, respectively, to select the promising skeletons from more than 45 reviewed compounds isolated from mushrooms in the last decade. Using rigid and flexible molecular docking approaches such as induced fit docking (IFD) in the binding sites of β-secretase (BACE1) and acetylcholine esterase (ACHE), promising structures were screened through high precision molecular docking compared with standard drugs donepezil and (2E)-2-imino-3-methyl-5,5-diphenylimidazolidin-4-one (OKK) using Maestro and Cresset Flare platforms. Molecular interactions, binding distances, and RMSD values were measured to reveal key interactions at the binding sites of the two neurodegenerative enzymes. Analysis of IFD results revealed consistent bindings of dictyoquinazol A and gensetin I in the pocket of 4ey7 while inonophenol A, ganomycin, and fornicin fit quite well in 4dju demonstrating binding poses very close to native ligands at ACHE and BACE1. Respective key amino acid contacts manifested the least steric problems according to their Gibbs free binding energies, Glide XP scores, RMSD values, and molecular orientation respect to the key amino acids. Molecular dynamics simulations further confirmed our findings and prospected these compounds to show significant in vitro results in their future pharmacological studies.

Ir(I)-Bi(III) Donor-Acceptor Adducts Stabilized by Dispersion Interactions between the Metal Pincer Ligands and Their Possible Self-Assembly Forming Molecular 1D Semiconductors.

Structure, stability, and electronic properties of the bimetallic {[IrI(terpy)(Me)]-[BiIIINNN]}n monomeric, oligomeric, and polymeric structures (n = 1-3 and ∞; terpy = terpyridine; Me = methyl; BiNNN = bismuth triamide) and their derivatives (designated as (Bi·Ir)n structures) were studied theoretically by DFT cluster and periodic calculations. Stable Bi·Ir adducts (monomers) were formed with short Bi-Ir bonds (<2.7 Å) and Gibbs free binding energies larger than 20 kcal/mol for all systems. The substitution of the pincer ligands of Ir(I) and Bi(III) complexes by the electron-donating (NH2) and electron-withdrawing (NO2, F, CF3) groups, respectively, enhanced the Ir → Bi charge transfer, substantially stabilizing the Bi·Ir monomers. The monomers from the unsubstituted complexes can be considered as dispersion stabilized adducts, and they may form spontaneously (Bi·Ir)n layered oligomers/polymers with semiconducting properties. The self-assembly of monomers into oligomers/polymers is hindered by bulkier protecting groups on the Bi(III) complex, such as tBu and SiMe3.

Physicochemical investigations of nootropic drug piracetam for enhanced solubilization as nano drug carrier under the influence of single and mixed micellar formulations: An optimized approach towards drug delivery

Nonionic surfactants have drawn tremendous attention for micellar solubilization, sustained release of the drug, encapsulation of pharmaceutically active ingredients, and permeabilization due to their distinct physicochemical characteristics. Concise solubility investigations are required for the appropriate selection of nonionic surfactant that is to be used for a formulation. In the present research, a cluster of micelles was developed that relies on trapping and stabilizing piracetam by balancing the hydrophilic and hydrophobic forces of nonionic surfactants. Tween 80 and Triton-X 100 and a mixture of these surfactants were used to clarify the drug-surfactant interaction in an aqueous and micellar medium. The interaction was investigated in premicellar, micellar, and post-micellar regions by using UV/Visible spectroscopy. Spectroscopic parameters were calculated to determine the degree of solubilization in terms of the partition coefficient (Kx), binding constant (Kb), and their respective energies in terms of Gibbs free energy of partition (ΔGp) and Gibbs free energy of binding (ΔGb) for piracetam. The solubilization of piracetam is enhanced by mixing an adequate amount of both nonionic surfactants. The obtained results demonstrated that solubilization is spontaneous and entropically favorable and the cluster of micelles in both single and mixed micellar mediums are stable due to the presence of a much more hydrophobic and hydrophilic culture which provides a synergistic link between the two surfactants.

Flavonoids as dual-action agents for anticancer and anti-tooth caries: a molecular docking and dynamics simulation on MMP2 inhibition

Objective: Cancer pathogenesis is linked to matrix metalloproteinase-2 (MMP2). Numerous studies have indicated an elevated expression of MMP2 in the tissue microenvironment of different cancers, including breast, oral, prostate, ovarian, colorectal, bladder, lung, and hepatocellular carcinoma. The significant role of MMP2 in the degradation of organic compounds in dentin, causing dental caries, has been indicated by accumulating evidence. This study explored the possibility of using flavonoids as natural compounds capable of inhibiting MMP2 to meet the need for new and potent MMP2 inhibitors. Methods: The AutoDock software evaluated the binding energies between selected flavonoids and the MMP2 catalytic domain and ranked the ligands based on their inhibition constant (Ki) values and Gibbs free binding energy scores. The Discovery Studio Visualizer tool demonstrated how the highest-ranked flavonoids interact with the MMP2. Molecular dynamics was conducted for the most potent MMP2 inhibitor in a 100 ns computer simulation. Results: Kaempferol 3-rutinoside-7-sophoroside demonstrated an inhibitory effect against MMP2 with a Ki value and ΔGbinding score of 209.92 fM and −17.30 kcal/mol, respectively. This flavonoid was able to restrict MMP2 activity within a femtomolar range. This study identified eight flavonoids with Ki values in the picomolar range. According to the study, the docked pose of kaempferol 3-rutinoside-7-sophoroside within the MMP2 catalytic domain reached stability after a simulation of ~60 nanoseconds. Conclusion: Inhibition of MMP2 by flavonoids, notably kaempferol derivatives, might be an effective therapeutic strategy for cancer treatment.

The interaction between formylphenoxyacetic acid derivatives (chalcone and flavones) and ionic surfactants: Insights into binding constants, solubilisation and physiochemical properties

In this study, UV-vis spectroscopy was employed to investigate the interaction between formylphenoxyacetic acid (FPAA) and its derivatives (chalcone and flavones) with ionic surfactants (SDS, CTAB, and DTAB) in different physiological environments. Changes in the physiochemical properties of FPAA chalcone and flavones including binding constants, partitioning constants, and Gibbs free energy were observed which were influenced by the presence of ionic surfactants computed using mathematical models. The solubilization of the targeted compounds in the ionic surfactants was determined through the binding constant (Kb). The results of the present study indicated that electrostatic interactions played a significant role in the solubilization of the targeted compounds in SDS, CTAB, and DTAB. At pH 4.1, FPAA chalcone exhibited stronger binding affinity with SDS compared to CTAB and DTAB. However, at pH 7.4, chalcone showed stronger binding with DTAB compared to SDS, while negligible interaction with CTAB was observed at pH 7.4. The flavones demonstrated stronger binding with DTAB at pH 7.4 compared to SDS and CTAB and it exhibited strong bonding with CTAB at pH 4.1. The negative values of the Gibbs free energy for binding (ΔGb˚) and partitioning (ΔGp˚) constants displayed the spontaneity of the process. However, FPAA chalcone with SDS and FPAA flavones with DTAB furnished positive ΔGb˚, indicating a non-spontaneous process.

Probing scaffold size effects on multivalent lectin-glycan binding affinity, thermodynamics and antiviral properties using polyvalent glycan-gold nanoparticles.

Multivalent lectin-glycan interactions (MLGIs) are pivotal for viral infections and immune regulation. Their structural and biophysical data are thus highly valuable, not only for understanding their basic mechanisms but also for designing potent glycoconjugate therapeutics against target MLGIs. However, such information for some important MGLIs remains poorly understood, greatly limiting research progress. We have recently developed densely glycosylated nanoparticles, e.g., ∼4 nm quantum dots (QDs) or ∼5 nm gold nanoparticles (GNPs), as mechanistic probes for MLGIs. Using two important model lectin viral receptors, DC-SIGN and DC-SIGNR, we have shown that these probes can not only offer sensitive fluorescence assays for quantifying MLGI affinities, but also reveal key structural information (e.g., binding site orientation and binding mode) useful for MLGI targeting. However, the small sizes of the previous scaffolds may not be optimal for maximising MLGI affinity and targeting specificity. Herein, using α-manno-α-1,2-biose (DiMan) functionalised GNP (GNP-DiMan) probes, we have systematically studied how GNP scaffold size (e.g., 5, 13, and 27 nm) and glycan density (e.g., 100, 75, 50 and 25%) determine their MLGI affinities, thermodynamics, and antiviral properties. We have developed a new GNP fluorescence quenching assay format to minimise the possible interference of GNP's strong inner filter effect in MLGI affinity quantification, revealing that increasing the GNP size is highly beneficial for enhancing MLGI affinity. We have further determined the MLGI thermodynamics by combining temperature-dependent affinity and Van't Hoff analyses, revealing that GNP-DiMan-DC-SIGN/R binding is enthalpy driven with favourable binding Gibbs free energy changes (ΔG°) being enhanced with increasing GNP size. Finally, we show that increasing the GNP size significantly enhances their antiviral potency. Notably, the DiMan coated 27 nm GNP potently and robustly blocks both DC-SIGN and DC-SIGNR mediated pseudo-Ebola virus cellular entry with an EC50 of ∼23 and ∼49 pM, respectively, making it the most potent glycoconjugate inhibitor against DC-SIGN/R-mediated Ebola cellular infections. Our results have established GNP-glycans as a new tool for quantifying MLGI biophysical parameters and revealed that increasing the GNP scaffold size significantly enhances their MLGI affinities and antiviral potencies.

Exploring natural anthraquinones as potential MMP2 inhibitors: A computational study

ObjectiveMatrix metalloproteinase-2 (MMP2) plays a significant role in cleaving extracellular matrix components, leading to many cancer cells' progression and invasion behavior. Therefore, MMP2 inhibition may hold promise for cancer treatment. Anthraquinones have shown antineoplastic effects, some of which have been used in clinical practice as anticancer drugs. This study used a computational drug discovery approach to assess the possible inhibitory effects of selected anthraquinones on MMP2. The results were then compared with that of Captopril, which was considered a standard drug. MethodsThis study used the AutoDock 4.0 tool to evaluate the binding affinity of 21 anthraquinones to the MMP2 catalytic domain. The most favorable scores based on the Gibbs free binding energy scores were given to the highest-ranked ligands. The Discovery Studio Visualizer tool illustrated interactions between MMP2 residues and top-ranked anthraquinones. ResultsA total of 12 anthraquinones were identified with ΔGbinding scores less than − 10 kcal/mol. Pulmatin (Chrysophanol-8-glucoside) was the most potent MMP2 inhibitor, with a ΔGbinding score of − 12.91 kcal/mol. This anthraquinone was able to restrict MMP2 activity within a picomolar range. ConclusionMMP2 inhibition by anthraquinones, notably Pulmatin, may be a useful therapeutic approach for cancer treatment.

PH-driven preparation of pea protein isolate-curcumin nanoparticles effectively enhances antitumor activity

Soluble pea protein isolate-curcumin nanoparticles were successfully prepared at a novel pH combination, with encapsulation efficiency and drug loading amount of 95.69 ± 1.63 % and 32.73 ± 0.56 μg/mg, respectively, resulting in >4000-fold increase in the water solubility of curcumin. The encapsulation propensity and interaction mechanism of pea protein isolates with curcumin and colchicine were comparatively evaluated by structural characterization, molecular dynamics simulations and molecular docking. The results showed that the nanoparticles formed by curcumin and colchicine with pea protein isolates were mainly driven by hydrogen bonding and hydrophobic interactions, and the binding process did not alter the secondary structure of pea protein. In contrast, pea protein isolate-curcumin nanoparticles exhibited smaller particle size, lower RMSD value, lower binding Gibbs free energy and greater structural stability. Therefore, pea protein isolate is a suitable encapsulation material for hydrophobic compounds. Furthermore, the pea protein isolate-curcumin nanoparticles showed remarkably enhanced antitumor activity, as evidenced by a significant reduction in IC50, and the anti-tumor mechanism of it involved the ROS-induced mitochondria-mediated caspase cascade apoptosis pathway. These findings provide insights into the development of pea protein-based delivery systems and the possibility of a broader application of curcumin in antitumor activity.

Evaluating the binding ability of promethazine hydrochloride drug with sodium dodecylsulphate/sodium lauroylsarcosinate/sodium cholate in the company of uridine biomolecules: experimental and theoretical approach

The appraisal of drug–surfactant binding interactions is pharmacologically and pharmaceutically noteworthy. The simple model compounds of nucleic acids such as nucleic acid bases/nucleosides are key biologically active molecules useful for studying interactions of nucleic acids with other components in bio-fluids. Therefore, the binding studies of promethazine hydrochloride (PMT) drug with individual surfactants such as sodium dodecylsulphate (SDS, anionic surfactant), sodium lauroylsarcosinate (SLS, amino based-surfactant), and sodium cholate (NaC, trihydroxy bile salt), and their mixed systems (PMT + SDS/SLS/NaC) at mole fractions, α PMT = 0.02, 0.04, 0.06, and 0.08 have been accomplished in water and 0.025 mol kg−1 aqueous uridine (nucleoside) solutions at temperatures (298.15, 308.15, and 318.15) K. Thermodynamic characteristics of micellization have been obtained from the conductivity studies. Binding constants (K b, K f) and standard Gibbs free energies of binding (ΔG ο b, ΔG ο f) for pure PMT drug and its mixed systems with anionic surfactants were evaluated from UV–visible absorption and fluorescence emission studies. Further, the density functional theory (DFT) calculations for studied systems were carried out to get net stabilization energies for the drug–surfactant complexes. NBO and HOMO–LUMO analyses were also carried out in the absence/presence of uridine. Dynamic light scattering study was used to measure the hydrodynamic diameters in micellar systems. The major influences of hydrophobic–hydrophobic interactions among the hydrophobic groups and electrostatic (ionic and H-bond) interactions among the hydrophilic/ionic groups of PMT drug, SDS/SLS/NaC, and uridine have been depicted from the present investigations.

MOLECULAR DYNAMICS SIMULATIONS OF THE AFFINITY OF CHITIN AND CHITOSAN FOR COLLAGEN: THE EFFECT OF pH AND THE PRESENCE OF SODIUM AND CALCIUM CATIONS

Chitosan and chitin are promising biopolymers used in many areas including biomedical applications, such as tissue engineering and viscosupplementation. Chitosan shares similar properties with hyaluronan, a natural component of synovial fluid, making it a good candidate for joint disease treatment. The structural and energetic consequences of intermolecular interactions are crucial for understanding the biolubrication phenomenon and other important biomedical features. However, the properties of biopolymers, including their complexation abilities, are influenced by the nature of the aqueous medium with which they interact. In this study, we employed molecular dynamics simulations to describe the effect of pH and the presence of sodium and calcium cations on the stability of molecular complexes formed by collagen type II with chitin and chitosan oligosaccharides. Based on Gibbs free energy of binding, all considered complexes are thermodynamically stable over the entire pH range. The affinity between chitosan oligosaccharide and collagen is highly influenced by pH, while oligomeric chitin shows no pH-dependent effect on the stability of molecular assemblies with collagen. On the other hand, the presence of sodium and calcium cations has a negligible effect on the affinity of chitin and chitosan for collagen.

Spectrophotometric investigation on interactions of dye with surfactant in aqueous as well as alcoholic media

The interaction of the methyl orange (MO) dye with cetyltrimethylammonium bromide (CTAB) in propanol, butanol, and water was studied using spectrophotometry method. The NLREG approach was used to compute the distribution constant which is the lower as carbon number increases which resembles that value of distribution constant 0.07161476, 0.00060913, 0.00010865 is of water, 1-propanol, 1-butanol media respectively. The Benesi-Hilderbrand and Hashemi and Sun equations were also used to determine the binding constant (Kb) and Gibbs free energy of binding (ΔG°). As the alkyl chain lengthened, the ΔG° value shifted more negatively in comparison to water. The spontaneous nature of CTAB binding with MO was suggested by the negative value of ΔG°. As the concentration of CTAB in the water & alcoholic media increased, the MO absorption dramatically blue-shifted from 464 nm (water) to 440–450 nm (propanol, butanol). These findings showed that the alkyl chain plays a role in reducing absorbance. The MO absorbance in the water, 1-propanol or 1-butanol media decreased with increasing CTAB concentration (hyperchromic shift).

"Reaction"-Like Shaping of Self-Delivery Supramolecular Nanodrugs in the Nanoprecipitation Process.

Nanoprecipitation, which is achieved through the diffusion and precipitation of drug molecules in blended solvent and antisolvent phases, is a classic route for constructing nanodrugs (NDs) and previously directed by diffusion-controlled theory. However, the diffusion-controlled mechanism is out of date in the recent preparation of self-delivery supramolecular NDs (SDSNDs), characterized by the construction of drug nanoparticles through supramolecular interactions in the absence of carriers and surfactants. Herein, a "reaction"-like complement, contributed from supramolecular interactions, is proposed for the preparation of naphthoquinone SDSNDs. Different from the diffusion-controlled process, the formation rate of SDSNDs via the "reaction"-like process is almost constant and highly dependent on the supramolecular interaction-determined Gibbs free energy of molecular binding. Thus, the formation rate and drug availability of SDSNDs are greatly improved by engineering the supramolecular interactions, which facilitates the preparation of SDSNDs with expected sizes, components, and therapeutic functions. As a deep understanding of supramolecular-interaction-involved nanoprecipitation, the current "reaction"-like protocol not only provides a theoretical supplement for classic nanoprecipitation but also highlights the potential of nanoprecipitation in shaping self-assembled, coassembled, and metal-ion-associated SDSNDs.

Strong Binding of C-Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds.

Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a C-glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of O-peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar Kd values. The best inhibitor displayed a Kd value of 8.0 μM. An analysis of the thermodynamic binding parameters revealed that the binding Gibbs free energy (ΔG) of the new inhibitors was dominated by enthalpy (ΔH). The binding mode of the four most efficient 1,2-thiodisaccharides was also studied by X-ray crystallography that uncovered the unique role of water-mediated hydrogen bonds in conferring enthalpy-driven affinity enhancement for the new inhibitors. This 1,2-thiodisaccharide-type scaffold represents a new lead for galectin-3 inhibitor discovery and offers several possibilities for further development.

Identifying potential inhibitors of C-X-C motif chemokine ligand10 against vitiligo: structure-based virtual screening, molecular dynamics simulation, and principal component analysis

The research aims to envisage small molecule inhibitors targeting the C-X-C motif chemokine ligand 10 (CXCL10) of the JAK/STAT pathway. CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway. To accomplish the aim, structure-based virtual screening with fundamental search limits, e.g., molecular weight (MW ≤ 500 Da), hydrogen bond donor (HBD ≤ 5), hydrogen bond acceptor (HBA ≤ 10), and lipophilicity (logP ≤ 5) was used to screen investigational molecules from MCULE database. The SBVS-ligand hits were sifted through toxicity profiling followed by filtration through the Brain or IntestinaL EstimateD-Egg model to check the human intestinal abortion and blood-brain barrier permeation based on two physicochemical properties, including topological surface area and WLOGP. The BOILED-Egg filtered compounds were passed through drug-likeness features other than Pfizer’s Lipinski rule of five, viz., Ghose filters, Muegge filters, Egan parameters, and Veber filters, followed by medicinal chemistry’s pan assay interference structure and Brenk alert investigation. Chemical compounds that comply with the above ADME descriptors were docked with target protein CXCL10 via AutoDock Vina. The stability of the top two ligand hits was assessed through dynamics simulations of 100 ns and principal component analysis and compared with the reference drugs Baicalein and EGCG. Based on the findings of Gibbs free energy of binding, ADME profiling, medicinal chemistry attributes depiction, root-mean-square deviation, root-mean-square fluctuation, solvent accessible surface area, the free energy of solvation, the radius of gyration, and PCA, MCULE2726078782-0-2 was found better than potential reference drug Baicalein. Communicated by Ramaswamy H. Sarma

Computer-aided Design of New Hydroxamic Acid Derivatives Targeting the Plasmodium falciparum M17 Metallo-aminopeptidase with Favorable Pharmacokinetic Profile

Through structure-based molecular design, we virtually design new subnanomolar range antimalarial, inhibitors of Plasmodium falciparum M17 aminopeptidase (PfA-M17). We developed the complexation QSAR models from hydroxamic acid derivatives (HDA). A linear correlation was established between the computed Gibbs free energies of binding (GFE: ΔΔGcom) and observed enzyme inhibition constants (Ki exp) for each training set pKi exp = , R2 = 0.97. The predictive power of the QSAR model was validated with 3D-QSAR pharmacophore generation (PH4): pKi exp = 0.707×pKi pred − 2.5182, R2 = 0.89. We then conducted a study on catalytic residues to exploit the different interactions (enzyme: inhibitor). Structural information from the models guided us in designing a virtual combinatorial library (VCL) of more than 56 thousand HDAs. The PH4 screening retained 48 new and potent HDAs with predicted inhibitory potencies pKi pre up to 73 times lower than that of HDA1 (pKi exp = 2.5 nM). Combining molecular modeling and PH4 in-silico screening of the VCL resulted in the proposed novel potent antimalarial agent candidates with favorable pharmacokinetic profiles.

Density Functional Theory Computation and Machine Learning Studies of Interaction between Au3 Clusters and 20 Natural Amino Acid Molecules.

The optimal adsorption sites and the binding energies of neutral Au3 clusters with 20 natural amino acids under the gas phase and water solvation were systematically investigated based on density functional theory (DFT) calculations. The calculation results showed that in the gas phase Au3 tends to bind with N atoms of amino groups in amino acids, except methionine, which tends to bind with Au3 through S atoms. Under water solvation, Au3 clusters tended to bind to N atoms of amino groups and N atoms of side chain amino groups in amino acids. However, methionine and cysteine bind more strongly to the gold atom through the S atom. Based on the binding energy data of Au3 clusters and 20 natural amino acids under water solvation calculated by DFT, a machine learning model (gradient boosted decision tree) was proposed to predict the optimal binding Gibbs free energy (ΔG) of the interaction between Au3 clusters and amino acids. The main factors affecting the strength of the interaction between Au3 and amino acids were uncovered by the feature importance analysis.

Deciphering the structure of a distinctive trimodular cellulosomal licheninase (RfGH16_21), a family 16 glycoside hydrolase from Ruminococcus flavefaciens by computational and experimental methods

In order to know the insights of a unique naturally existing trimodular licheninase from GH16 family, sub-family 21 (RfGH16_21) from Ruminococcus flavefaciens, its structure was modeled to understand its functional relations to reveal information regarding modifying the enzyme for improved properties with enhanced catalytic efficiency. Homology modeling revealed three tandem repeats of β-jelly roll like folds linked by natural linkers. Catalytic pockets and the catalytically important amino acids in each tandem repeat of RfGH16_21 determined by multiple sequence alignment and structure superposition with its homologues indicated that two Glu residues are involved in a retaining-type of catalytic mechanism. Sequential molecular docking revealed maximum binding energy with mixed linked cellotriose showing that cellotriose is the lowest oligomeric hydrolysed product formed by the catalytic action of endo-β-1,3–1,4-glucanase. Molecular dynamic (MD) simulation of RfGH16_21-cellotriose complex confirmed the structural specificity of catalytic residues and increased stability of enzyme in presence of ligand as compared to simulated RfGH16_21 alone. The binding affinity of cellotriose towards the three tandem repeats of RfGH16_21 was also confirmed by calculating total binding Gibbs free energy, i.e. −100.8 ± 2.6 KJ/mol, by using g_mmpbsa tool. The stability of the protein was determined by protein melting analysis that showed Ca2+ and Mg2+ ions imparted structural stability to RfGH16_21. Dynamic light scattering analysis of RfGH16_21 showed monodispersity and hydrodynamic radius of 4.0 nm at 2.0 mg/mL protein concentration, which was comparable with the radius of gyration of 3.2 nm determined by MD simulation showing the protein to be in monomeric form. Communicated by Ramaswamy H. Sarma

Synthesis, molecular docking, and binding Gibbs free energy calculation of β-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease

The outbreak of novel coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (SARS-CoV-2), has had a significant impact on human health and the economic development. SARS-CoV-2 3CL protease (3CLpro) is highly conserved and plays a key role in mediating the transcription of virus replication. It is an ideal target for the design and screening of anti-coronavirus drugs. In this work, seven β-nitrostyrene derivatives were synthesized by Henry reaction and β-dehydration reaction, and their inhibitory effects on SARS-CoV-2 3CL protease were identified by enzyme activity inhibition assay in vitro. Among them, 4-nitro-β-nitrostyrene (compound a) showed the lowest IC50 values of 0.7297 µM. To investigate the key groups that determine the activity of β-nitrostyrene derivatives and their interaction mode with the receptor, the molecular docking using the CDOCKER protocol in Discovery Studio 2016 was performed. The results showed that the hydrogen bonds between β-NO2 and receptor GLY-143 and the π-π stacking between the aryl ring of the ligand and the imidazole ring of receptor HIS-41 significantly contributed to the ligand activity. Furthermore, the ligand-receptor absolute binding Gibbs free energies were calculated using the Binding Affinity Tool (BAT.py) to verify its correlation with the activity of β-nitrostyrene 3CLpro inhibitors as a scoring function. The higher correlation(r2=0.6) indicates that the absolute binding Gibbs free energy based on molecular dynamics can be used to predict the activity of new β-nitrostyrene 3CLpro inhibitors. These results provide valuable insights for the functional group-based design, structure optimization and the discovery of high accuracy activity prediction means of anti-COVID-19 lead compounds.

Interaction of Methyl Red with Cetylpyridinium Chloride in Methanol-Water System

The interaction between methyl red (azo dye) and cetylpyridinium chloride (cationic surfactant) in the methanol-water system were studied using a spectrophotometric technique. Variable parameters like constant dye concentration and its structure, surfactant concentration, pH, absorbance, and solvent composition were studied. Using the UV-Vis technique, critical micelle concentrations (CMCs) of cetylpyridinium chloride were measured with methyl red. The spectral data were analyzed and determined the differential absorbance, binding and partition constants, partition coefficient, the Gibbs free energy of binding and partition in mixed solvent media (0.1, 0.2, 0.3, 0.4 volume fraction (v.f.)s of methanol, respectively).

Computational Modeling on Binding Interactions of Cyclodextrin s with the Human Multidrug Resistance P-glycoprotein Toward Efficient Drug-delivery System Applications.

Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: α-CD, β-CD, and γ-CD) family with potential pharmacological relevance and the multidrug resistance P-gp protein toward efficient drug-delivery applications. The treatment of neurological disorders and cancer therapy where the multiple drug-resistance phenomenon mediated by the P-gp protein constitutes the fundamental cause of unsuccessful therapies. To understand more about the CD docking mechanism and the P-gp. In order to achieve the main goal, the computational docking process was used. The observed docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions,and also hybrid electrostatic/side-chain interactions of the CD-ligands' OHmotifs with acceptor and donor characteristics, which might theoretically cause local perturbations in the TMD/P-gp inter-residues network, influencing ligand extrusion through the blood-brain barrier. P-gp residues were conformationally favored. Despite the structural differences, all the cyclodextrins exhibit very close Gibbs free binding energy values (or affinity) by the P-gp binding site (transmembrane domains - TMDs). The obtained theoretical docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the OH-motifs of the CD-ligands with acceptor and donor properties which theoretically could induce allosteric local-perturbations in the TMDs-inter-residues network of P-gp modulating to the CD-ligand extrusion from the blood-brain-barrier (or cancer cells). Finally, these theoretical results open new horizons for evaluating new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine.