Binding Energies Of Complexes Research Articles

Naturally Occurring Plant-Based Anticancerous Candidates as Potential ERK2 Inhibitors: In-Silico Database Mining and Molecular Dynamics Simulations.

The evolutionarily conserved extracellular signal-regulated kinase 2 (ERK2) is involved in regulating cellular signaling in both normal and pathological conditions. ERK2 expression is critical for human development, while hyperactivation is a major factor in tumor progression. Up to now, there have been no approved inhibitors that target ERK2, and as such, here we report on screening of a naturally occurring plant-based anticancerous compound-activity-target (NPACT) database for prospective ERK2 inhibitors. More than 1,500 phytochemicals were screened using in-silico molecular docking and molecular dynamics (MD) approaches. NPACT compounds with a docking score lower than a co-crystallized LHZ inhibitor (calc.-10.5 kcal/mol) were subjected to MD simulations. Binding energies (ΔGbinding) of inhibitor-ERK2 complexes over the MD course were estimated using an MM-GBSA approach. Based on MM-GBSA//100 ns MD simulations, the steroid zhankuic acid C (NPACT01034) demonstrated greater binding affinity against ERK2 protein than LHZ, with ΔGbinding values of -50.0 and -47.7 kcal/mol, respectively. Structural and energetical analyses throughout the MD course demonstrated stabilization of zhankuic acid C complexed with ERK2 protein. The anticipated ADMET properties of zhankuic acid C indicated minimal toxicity. Moreover, in-silico evaluation of fourteen ERK2 inhibitors in clinical trials demonstrated the higher binding affinity of zhankuic acid C towards ERK2 protein.

Unveiling the therapeutic potential of epigallocatechin gallate in liver cancer: insights from network pharmacology and in vitro assays

Epigallocatechin gallate (EGCG) is a prominent catechin found in green tea polyphenols and has shown promising anti-tumor properties. However, the exact regulatory mechanism of EGCG on liver cancer is not fully revealed. In this study, we conducted integrative analyses using the SwissTargetPrediction and GeneCards repositories, which identified 98 targets. These targets were used to construct a protein-protein interaction network using STRING and visualised with Cytoscape. Central to this network are hub proteins, notably TNF and PIK3CA, suggesting pivotal roles in the therapeutic landscape. Gene Ontology (GO) enrichment analysis unveiled 1,570 biological terms with a notable preponderance within oxidative stress response processes. Complementary pathway enrichment via the Kyoto Encyclopaedia of Genes and Genomes (KEGG) highlighted 134 pathways, with the PI3K-Akt pathway emerging as prominent. In silico molecular docking supported these findings, revealing binding energies of EGCG-target complexes below −7.0 kcal/mol, indicative of robust interactions. Moreover, cellular assays including CCK-8, wound-healing, and Transwell modalities, established EGCG’s inhibitory concentration-dependent effects on HepG2 cell proliferation, migration, and invasion. Apoptotic assays affirmed by FACS, evidenced enhanced apoptosis with escalating EGCG concentrations, underpinned by modulations in caspase activity and apoptotic protein levels. Notably, Western blot analysis demonstrated the attenuation of the PI3K/AKT signalling cascade by EGCG, paralleling the inhibitory profile of LY294002. These multifaceted inhibitory effects underscore EGCG's potential as an anti-tumor agent, deploying a strategic blockade of oncogenic pathways and augmenting apoptotic mechanisms, which provide a strong rationale for its application in liver cancer therapeutics.

First-principles calculation of self-interstitial atom-impurity atom interactions in ferritic steel

In this study, the interactions between self-interstitial atoms (SIA) and impurity atoms (Cu and P) in the body-centered cubic (bcc)-Fe matrix have been investigated using the first principles approach. The results show that Cu and P atoms are more prone to segregation on perpendicular and parallel surfaces containing dumbbell atoms, respectively. Next, by combining the charge density difference and considering the electronic structure and lattice distortion, the origin of the binding energy of complexes formed between SIA and impurity atoms was discussed. The results show that as the number of impurity atoms increases, the atomic bonds formed by the interactions between the impurity atoms decrease the binding energy between single impurity atoms and the matrix and reduce the strain field around them, resulting in an increase in the stability of the complexes. Comparison with previous experimental results revealed the reasons for the changes in atomic occupancy during the segregation of Cu and P atoms. The results provide insights into the behavior of impurity atoms in irradiated materials and provide a deeper understanding of the electron level of impurity atomization.

Designing of xanthine-based DPP-4 inhibitors: a structure-guided alignment dependent Multifacet 3D-QSAR modeling, and molecular dynamics simulation study

The DPP-4 enzyme degrades incretin hormones GLP-1 and GIP. DPP-4 inhibitors are found effective in the prevention of the degradation of incretins. Xanthine scaffold-bearing molecules are reported as potential DPP-4 inhibitors for treating type 2 diabetes mellitus, e.g. the marketed drug linagliptin. In this work, structure-guided alignment-dependent atom- and Gaussian field-based 3D-QSAR have been performed on a dataset of 75 molecules. The robustness and predictive ability of the developed multifacet 3D-QSAR models were validated on different statistical parameters and found to be statistically fit. The favorable and unfavorable pharmacophoric features were mapped for each multifacet 3D-QSAR model based on three alignment sets (1–3). A five-point common pharmacophore hypothesis was generated separately for each set of alignments. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (Compounds 12, 40 and 57) compared to reference standard linagliptin to study the binding energy and stability of target-ligand complexes. The MM-PBSA calculations revealed that the binding free energy and stability of compounds 12 (−40.324 ± 17.876 kJ/mol), 40 (−80.543 ± 21.782 kJ/mol) and 57 (−50.202 ± 16.055 kJ/mol) were better than the reference drug linagliptin (−20.390 ± 63.200 kJ/mol). The generated contour maps from structure-guided alignment-dependent multifacet 3D-QSAR models offer information about the structure–activity relationship (SAR) and ligand-target binding energy and stability data from MD simulation may be utilized to design and develop target selective xanthine-based novel DPP-4 inhibitors. Communicated by Ramaswamy H. Sarma

Identification of phytocompounds as potent inhibitors of sodium/glucose cotransporter-2 leading to diabetes treatment

Type-II diabetes, a major metabolic disorder has threatened the very existence of a healthy life since long ago. Commercially available antidiabetic drugs are known for several adverse effects. The present study attempted to identify potential phytocompounds as inhibitors of sodium/glucose cotransporter-2 (SGLT2), a major protein that helps in glucose re-absorption from renal tubules. A total of 28 phytocompounds were collected based on the literature survey. 3D co-ordinates of phytocompounds were collected from PubChem database. Molecular docking was carried out with SGLT2 protein and the best 3 docking complexes were subjected to molecular dynamics simulation for 100 ns. Free energy changes were also analyzed using MM/PBSA analysis. Phytocompounds were also analyzed for their drug-likeness and ADMET properties. Docking study observed a strong binding affinity of phytocompounds (> −7.0 kcal/mol). More than 10 phytocompounds showed better binding affinity compared to reference drugs. Further analysis of three best docking complexes when analyzed by MD simulation showed better stability and compactness of the complexes compared to reference drug, empagliflozin. MM/PBSA analysis also revealed that van der Waals force and electrostatic energy are the major binding energy involved in the complex formation. Like docking energy, free energy analysis also observed stronger binding energies (ΔGGAS) in SGLT2-phytocompound complexes compared to empagliflozin complex. All the phytocompounds showed drug-likeness and considerable ADMET properties. The study, therefore, suggests that Trifolirhizin-6′-monoacetate, Aspalathin, and Quercetin-3-glucoside could be a possible inhibitor of SGLT2 protein. However, further studies need to be carried out to reveal the exact mode of activity. Communicated by Ramaswamy H. Sarma

Non-covalent binding interaction of bioactive coumarin esculetin with calf thymus DNA and yeast transfer RNA: A detailed investigation to decipher the binding affinities, binding location, interacting forces and structural alterations at a molecular level

Esculetin is a well-known coumarin derivative found abundantly in nature possessing an extensive array of pharmacological and therapeutic properties. Consequently, to comprehend its molecular recognition mechanism, our objective is to conduct a complete investigation of its interactions with the nucleic acid, specifically ct-DNA, and t-RNA, using spectroscopic and computational techniques. The intrinsic fluorescence of esculetin is quenched when it interacts with ct-DNA and t-RNA, and this occurs through a static quenching mechanism. The thermodynamic parameters demonstrated that the interaction is influenced by hydrogen bonding and weak van der Waals forces. CD and FT-IR results revealed no conformational changes in ct-DNA and t-RNA structure on binding with esculetin. Furthermore, competitive displacement assay with ethidium bromide, melting temperature, viscosity measurement, and potassium iodide quenching experiments, reflected that esculetin probably binds to the minor groove of ct-DNA. The molecular docking results provided further confirmation for the spectroscopic findings, including the binding location of esculetin and binding energies of esculetin complexes with ct-DNA and t-RNA. Molecular dynamics simulation studies demonstrated the conformational stability and flexibility of nucleic acids.

Synthesis, characterization, structural elucidation, molecular docking and antidiabetic studies of 1,10-phenanthroline based mononuclear Cu(II) and Zn(II) complexes

Three new mononuclear mixed ligand copper(II) and zinc(II) complexes were synthesized having general formulae [Cu (L1) (L2)2] (1), [Cu2 (L3) (L2)2] (2), [Zn (L3)2 (L2)] (3), where L1 = 3, 4-dichloro phenylacetate, L2 = 1, 10-phenathroline and L3 = 2-bromophenylacetate. All the complexes were structurally characterized by FT-IR and single crystal X-ray diffraction analysis. Compound 1 is penta-coordinated where Cu(II) ion is surrounded by 3, 4-dichlorophenyacetate and two 1,10-phenanthroline moities. Compound 2 has hexa-coordinated Cu(II) surrounded by two 1,10-phenanthroline moieties and a 2-bromophenylacetate. Compound 3 is hexa-coordinated Zn(II) complex surrounded by 1,10-phenanthroline and two 2-bromophenylacetate moities. DNA binding mechanism of all complexes was examined by molecular docking studies. Based on molecular bonding results the binding energies for complexes 1–3 were found to be −5.86 kcal/mol, −5.81 kcal/mol and −5.85 kcal/mol, respectively. These stable complexes indicated spontaneous interaction ability with DNA which may have further biological potential. This has been supported by the in-vitro DNA-binding activity of the complexes as well using spectrophotometry. All the complexes were subjected for their anti-diabetic potential. All the complexes exhibited potent inhibitory capability against the α-glucosidase with IC50 values in the range of 2.63–6.19 µM compared with the available marketed drug acarbose (IC50 = 873.34 ± 1.67 µM).

Induction of ferroptosis cell death in acute promyelocytic leukemia cell lines (NB4 and HL-60) using hydrothermally synthesized ZnO NPs in the presence of black cardamom extract

This paper reports an effective, one-step, and eco-friendly method for producing ZnO nanoparticles (NPs) via the hydrothermal procedure. In the synthesis procedure, where 1,8-cineole is the dominant component, an optimized concentration of black cardamom extract is utilized as a capping and reducing agent. The decision to use this extract can be justified because it has a quick reducing capacity. Scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), Dynamic Light Scattering (DLS), and Fourier-transform infrared spectroscopy (FT-IR) have all been used to analyze the NPs. Furthermore, healthy cells (PBMCs) and the Acute Promyelocytic Leukemia cell lines (NB4 and HL-60) were treated to varied concentrations of ZnO NPs for 24 and 48 h. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) test was then used to determine the cell viability. Oxidative and ferroptosis markers were evaluated using commercial kits. Gene expression and cell death were measured using qRT-PCR and flow cytometry. Also, the binding energy and van der Waals interactions of ZnO NP-protein complexes were calculated using molecular docking. On leukemic cells, ZnO NPs displayed growth-inhibiting effects in a time and dose-dependent manner. By considerably boosting lipid-ROS, intracellular iron, ACSL4, and p53 while significantly lowering GSH and GPx activity levels, as well as SLC7A11 and GPx4 mRNA, the ZnO NPs accelerated the ferroptotic cell death. On the other hand, ZnO NPs showed no toxicity to healthy cells. So, based on our research, synthesized ZnO NPs can induce ferroptotic cell death in leukemic cells.

Successful preparation of tercopolymer hydrogel for the removal of toluidine dye from contaminated water: Experimental and DFT study

ABSTRACT Polymeric hydrogel with pH-sensitive surface was prepared in this study. The surface morphologies of the synthesized materials were examined using scanning electron microscopy. Surface area and pore sizes of the hydrogels were determined using Brunauer–Emmett–Teller. Fourier transform infra-red spectroscopy was used for the identification of various functional groups on the surface of these adsorbents. These hydrogels were extremely efficient in removing toxic toluidine dye from contaminated water. Kinetics and isothermal models were used for the calculations of adsorption parameters of the synthesized materials. The adsorption data were impeccably explained with pseudo‐second order and the Langmuir model as compared to other models. The spontaneity of the reaction was confirmed by thermodynamic study. In this study the value of enthalpy (∆H°) was 7322.6 kJ/mol. The values of Gibbs energy (∆G°) were −453.9, −984.4 and −1515.2 kJ/mol, at 293K, 313K and 333K, respectively, for toluidine dye, which showed that the process is endothermic and spontaneous in nature. Moreover, the value for entropy (∆S°) was calculated as 26.54 Jmol/K for toluidine dye. The interactions of various functional groups on the surface of adsorbent and toluidine dye molecules were studied with density functional theory simulations. The large binding energies (−5.73 to −25/74 kcal/mol) of different complexes showed that the hydrogels had strong affinity for the adsorption of toluidine dye molecules while the negative values revealed that the process is spontaneous and endothermic. These results were consistent with the experimental results. This study revealed that the synthesized hydrogel is efficient adsorbent material for toluidine dye removal from contaminated water. The adsorption capacity of the prepared hydrogel was 526 mg/g for toluidine dye.

Theoretical Investigation of the Structures and Energetics of (MX)-Ethanol Complexes in the Gas Phase

The structures and energy of alkali halide salt (MX) complexes with ethanol have been investigated in this work. The core of this study is to explore the effect of ion size on the interactions between solvent and solute. LiF and KBr as monovalent salts with different sizes of inion and cation have been chosen to explore this difference in addition to various physical properties. Three complexes of each LiF and KBr with ethanol taking the formula MX(CH3CH2OH)n (n=1-3), were studied. Ab-initio calculations have been performed to optimize the chemical structures of these complexes and explore the possible structures, isomers, and their corresponding IR spectra using Density functional theory (DFT/ B3LYP). 6-311G** were chosen as basis sets for these calculations. The geometry evaluations, energy searches, vibrational frequency calculations, and each complex's binding energy were also theoretically extracted in this study. The minimum energy structures were calculated, and different isomers were found. The presence of Ionic hydrogen bonds (IHBs) was observed and proposed to be the main binding between the MX salt and ethanol. Also, the infrared vibrational bands in the OH stretching region were recorded for the minimum structures, and the determined red-shift was at about 400 cm-1. In addition, the binding energy calculations found a gradual rise in the BE value with every additional ethanol molecule added to MX salt.

Modeling coarse-grained van der Waals interactions using dipole-coupled anisotropic quantum Drude oscillators.

The Quantum Drude Oscillator (QDO) model is a promising candidate for accurately calculating the van der Waals (vdW) interaction. Anisotropic QDO models have recently been used to represent quantum fluctuations of molecular fragments rather than that of single atoms. While this model promises accurate calculation of vdW energy, there is significant room for improvements, such as incorporating a proper fragmentation method, higher-order dispersion corrections, and so forth. The present work attempts to gauge dipole-dipole interactions' ability without fragmentation. A suitable anisotropic damping function is also introduced to work with anisotropic QDO. This revised model accurately predicts the binding energies of vdW complexes for most of the systems considered. This work indicates the limit of dipole approximation for an anisotropic QDO-based model.

Excitons and trions with negative effective masses in two-dimensional semiconductors

AbstractWe study theoretically fundamental Coulomb-correlated complexes: neutral and charged excitons, also known as trions, in transition metal dichalcogenides monolayers. We focus on the situation where one of the electrons occupies an excited, high-lying, conduction band characterized by a negative effective mass. We develop the theory of such high-lying excitons and trions with negative effective mass and demonstrate the key role of the non-parabolicity of the high-lying conduction band dispersion in the formation of the bound exciton and trion states. We present simple, accurate and physically justified trial wavefunctions for calculating the binding energies of Coulomb-bound complexes and compare the results of variational calculations with those of a fully numerical approach. Within the developed model, we discuss recent experimental results on the observation of high-lying negative effective mass trions.

Evaluation of Antimalarial Activity of Ethanolic Extract of Annona muricata L.: An in vivo and an in silico Approach.

In Nigeria, Annona muricata L. has been used to treat a variety of ailments. The mechanism of the antimalarial activity of ethanolic leaf extract of Annona muricata (EEAML) was investigated using both an in vivo and an in silico approach. The experimental mice were divided into five groups: A-F. The mice in groups B-F were inoculated with Plasmodium berghei NK-65 and treated accordingly. Groups A and B are the negative and positive controls (infected and untreated), respectively. Group C received 10 mg/kg chloroquine (standard drug), whereas groups D-F received 100, 200, and 300 mg/kg body weight of the extract orally respectively. The mice were euthanized eight days after infection, and their liver and blood were collected and used in biochemical tests. Molecular docking was performed using the extract's HPLC compounds and Plasmodium falciparum proteins. In the suppressive, prophylactic, and curative tests, there was a significant decrease (p < 0.05) in parasitemia levels in groups treated with the extract compared to the positive control and standard drug. When compared to the positive control, there was a significant (p < 0.05) reduction in liver MDA, total cholesterol, and total triglyceride levels. The binding energies of luteolin and apigenin-pfprotein complexes were significantly (p < 0.05) higher compared to their respective references. The anti-plasmodial activity of the extract may result from its hypolipidemic effect, which deprives the parasite of essential lipid molecules needed for parasite growth, as well as from the inhibitory effects of apigenin and luteolin on specific proteins required for the Plasmodium metabolic pathway.

AN In-silico MOLECULAR DOCKING STUDY ON THE INTERACTION OF DIFFERENT PARABEN ESTERS (METHYL-, ETHYL-, PROPYL- AND BUTYL-PARABEN) WITH HUMAN THYROID HORMONE RECEPTOR α1 (THRα1) AND β1 (THRβ1)

Thyroid hormones (THs) activate transcription of a large number of genes via binding with nuclear thyroid hormone receptors (THRs) that are either attached to the DNA genetic strands or located in proximity to them. However, the ever-increasing human anthropogenic activities have introduced numerous harmful chemicals in the environment, many of which share high degree of structural resemblance with the THs i.e., triiodothyronine (T3) and thyroxine (T4) and thus can interfere with the normal downstream receptor signalling. The present study used bioinformatics to perform a molecular docking analysis (Autodock 4.2.6) where different paraben esters (PBs) i.e., methyl- (MP), ethyl- (EP), propyl- (PP) and butyl- paraben (BP) were examined for their possible interaction with two human THR isoforms viz., THRα1 and THRβ1. Perceiving the free binding energies (ΔG) of different PB-THRs complexes, it has become evident that BP has the strongest binding interaction with both THRα1 (PDB Id- 1NAV) and THRβ1 (PDB Id- 1NAX) i.e., -6.51 and -6.14 kcal/mol respectively and also has highest number of amino acids interactions in the active sites, followed by PP, EP and MP. The co-crystal ligand exhibited binding energies of -10.43 and -10.52 kcal/mol for THRα1 and THRβ1 respectively. Therefore, the study firmly demonstrates that thyroid hormone receptor interaction of the selected PB esters rise with increase in length/complexity of the alkyl side chain. Given that all the investigated PB esters are capable binders of both the THRs, unremitting use of these chemical preservatives certainly could amend the receptor mediated signalling of THs.

Structural analysis and electronic properties of transition metal ions (Ni2+, Fe2+, Mn+ and Co+) with psoralen biomolecule as an anticancer drug

In the current research, the density functional theory (DFT) method is used to investigate the effects of cation-π interaction on complexes formed by psoralen drug with metal cations (Ni2+, Fe2+, Mn+ and Co+). The calculations are performed in the gas phase and the water and carbon tetrachloride (CCl4) solvents. The interactions generated in the complexes are analyzed using the atoms in molecules (AIM) and the natural bond orbital (NBO) approaches. The results indicate that the absolute amount of the binding energy of complexes in the polar solvent is less than the non-polar solvent while in the gas phase it is more than solution. The obtained data also show that with increasing polarity of the solvent, the stabilization energy of the complexes increases. To gain a better insight into the mentioned interactions, the descriptors of chemical reactivity such as energy gap, hardness, softness and electronic chemical potential are also explored. Our findings display that the studied complexes have high chemical stability and low chemical reactivity in the solution relative to the gas phase.

A Cost Effective Scheme for the Highly Accurate Description of Intermolecular Binding in Large Complexes.

There has been a growing interest in quantitative predictions of the intermolecular binding energy of large complexes. One of the most important quantum chemical techniques capable of such predictions is the domain-based local pair natural orbital (DLPNO) scheme for the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)], whose results are extrapolated to the complete basis set (CBS) limit. Here, the DLPNO-based focal-point method is devised with the aim of obtaining CBS-extrapolated values that are very close to their canonical CCSD(T)/CBS counterparts, and thus may serve for routinely checking a performance of less expensive computational methods, for example, those based on the density-functional theory (DFT). The efficacy of this method is demonstrated for several sets of noncovalent complexes with varying amounts of the electrostatics, induction, and dispersion contributions to binding (as revealed by accurate DFT-based symmetry-adapted perturbation theory (SAPT) calculations). It is shown that when applied to dimeric models of poly(3-hydroxybutyrate) chains in its two polymorphic forms, the DLPNO-CCSD(T) and DFT-SAPT computational schemes agree to within about 2 kJ/mol of an absolute value of the interaction energy. These computational schemes thus should be useful for a reliable description of factors leading to the enthalpic stabilization of extended systems.

Exploration of Novel Mono Hydroxamic Acid Derivatives as Inhibitors for Histone Deacetylase Like Protein (HDLP) by Molecular Dynamics Studies

The acetylation modification process of histone has an essential role in the epigenetic regulation of gene expression. This process is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDACs are thought to be vital for cell function. Particularly, higher HDAC expression is frequent in various cancers, resulting in the dysregulation of several target genes involved in cell proliferation, differentiation, and survival. In this study, the inhibitory feasibility of several HDAC inhibitors was investigated, including vorinostat (SAHA), N-hydroxy-3-phenylprop-2-enamide (CPD1), N-hydroxy-3-(pyridine-4-yl)prop-2-enamide (CPD2), N-hydroxy-3-(pyridine-2-yl)prop-2-enamide (CPD3), 4-(diphenylamino)-N-(5-(hydroxyamino)-5-oxopentyl)benzamide (CPD4), 2-(6-(((6-fluoronaphthalen-2-yl)methyl)amino)-3-azabicyclo[3.1.0]hex-3-yl)-N-hydroxypirimidine-5-carboxamide (CPD5), and N-(3-aminopropyl)-N-hydroxy-2-((naphthalene-1-yloxy)methyl)oct-2-enediamide (CPD6). By examining the stability of the enzyme, positional stability of the individual amino acids, and binding energies of HDLP-inhibitor complexes, the inhibitory feasibility was assessed. The complexes of the HDLP enzyme with SAHA, CPD4, CPD5, and CPD6 had higher stability than the other studied complexes, according to the results of trajectory analysis and the Ramachandran plot. Based on the calculated MM-PBSA binding free energies, the stability of the HDLP enzyme followed this order CPD4 &gt; CPD5 &gt; SAHA &gt; CPD6 &gt; CPD2 &gt; CPD3 &gt; CPD1. The drugability values followed the same trend as the previous ones. Based on the obtained in silico results, CPD4, CPD5, and CPD6 were discovered to be possible lead compounds as reference inhibitors of SAHA.

Bioactive metabolites of edible mushrooms efficacious against androgenic alopecia: Targeting SRD5A2 using computational approach

IntroductionAndrogenic alopecia (AGA), scalp hair loss, occurs due to the hyperactivity of steroid 5α-reductase2 (SRD5A2), which metabolizes testosterone into 5α-dihydroxytestosterone. Finasteride, an FDA-approved drug producing many side effects, is a commonly used competitive inhibitor for SRD5A2 to treat AGA. As a number of mushroom species have been used to treat patients having hair loss problems since ancient times, in the present paper, the bioactive metabolites in mushrooms were computationally screened to assess SRD5A2 inhibitory properties and compared with Finasteride. MethodologyA virtual screening approach in conjunction with molecular dynamics simulation and MMPBSA methods has been applied to identify potential inhibitors against SRD5A2. SwissADME tool and AutoDock Vina were used to screen the library of 152 bioactive mushroom metabolites. All MD simulations were carried out using GROMACS 5.1.4 suite and GROMOS96 43a1 force field. The stability of SRD5A-ligand complexes was determined in terms of RMSD, RMSF, Rg, SASA, and hydrogen bonding. The binding energy of complexes was calculated using MMPBSA. Results and ConclusionVirtual screening and MD simulation studies revealed that out of the 152 metabolites, three bioactives, i.e., Zhankuic acid A (−11.5 kcal/mol), Sterenin M (−10.4 kcal/mol), Melleolide K (−10.2 kcal/mol), and drug Finasteride having the least binding energy are the potential inhibitors of SRD5A2. These molecules also exhibited stable interaction with SRD5A2 during MD simulation. This study will pave the way for the experimental evaluation and validation of the medicinal potentials of screened mushroom compounds to treat androgenic alopecia.

Identification and construction of a multi-epitopes vaccine design against Klebsiella aerogenes: molecular modeling study

A rapid rise in antibiotic resistance by bacterial pathogens is due to these pathogens adaptation to the changing environmental conditions. Antibiotic resistance infections can be reduced by a number of ways such as development of safe and effective vaccine. Klebsiella aerogene is a gram-negative, rod-shaped bacterium resistant to a variety of antibiotics and no commercial vaccine is available against the pathogen. Identifying antigens that can be easily evaluated experimentally would be crucial to successfully vaccine development. Reverse vaccinology (RV) was used to identify vaccine candidates based on complete pathogen proteomic information. The fully sequenced proteomes include 44,115 total proteins of which 43,316 are redundant and 799 are non-redundant. Subcellular localization showed that only 1 protein in extracellular matrix, 7 were found in outer-membrane proteins, and 27 in the periplasm space. A total of 3 proteins were found virulent. Next in the B-cell-derived T-cell epitopes mapping phase, the 3 proteins (Fe2+− enterobactin, ABC transporter substrate-binding protein, and fimbriae biogenesis outer membrane usher protein) were tested positive for antigenicity, toxicity, and solubility. GPGPG linkers were used to prepare a vaccine construct composed of 7 epitopes and an adjuvant of toxin B subunit (CTBS). Molecular docking of vaccine construct with major histocompatibility-I (MHC-I), major histocompatibility-II (MHC-II), and Toll-like receptor 4 (TLR4) revealed vaccine robust interactions and stable binding pose to the receptors. By using molecular dynamics simulations, the vaccine-receptors complexes unveiled stable dynamics and uniform root mean square deviation (rmsd). Further, binding energies of complex were computed that again depicted strong intermolecular bindings and formation of stable conformation.

Potential Mechanisms of Biejiajian Pill in the Treatment of Diabetic Atherosclerosis Based on Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation.

Background Biejiajian pill (BJJP), a classical traditional Chinese formula, has been reported that it has an effective treatment for diabetic atherosclerosis in recent years, but its underlying mechanisms remain elusive. The study aimed to explore the potential mechanisms of BJJP on diabetic atherosclerosis by integrating network pharmacology, molecular docking, and molecular dynamics simulation. Methods The active components of BJJP were collected by TCMSP and TCMID, and then the potential targets were obtained from the SwissTargetPrediction database. The targets related to diabetic atherosclerosis were identified from the GeneCards and OMIM databases. The intersection of the potential targets regulated by active components of BJJP and the targets of diabetic atherosclerosis were common targets, which were visualized by the Venn diagram. The common targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. The network of “Medicine-Compound-Target” was constructed with Cytoscape 3.7.1 software. GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using the DAVID database and visualized through bioinformatics. The intersecting targets were input into Cytoscape 3.7.1 software, and the Network Analyzer tool was employed to screen out the key targets. Then molecular docking was used to verify the binding affinity between the active compounds and the key targets, and molecular dynamics simulation was used to investigate the stability of the binding models. Results A total of 81 active components, 186 targets of BJJP, and 4041 targets of diabetic atherosclerosis were obtained. Furthermore, 121 overlapping targets were identified. GO functional enrichment analysis revealed that these targets were correlated with the oxidation-reduction process, negative regulation of apoptotic process, inflammatory response, and other biological processes. The results of the KEGG pathway enrichment analysis showed that the common targets mainly participated in proteoglycans in cancer, PPAR signaling pathway, adherens junction, insulin resistance, HIF-1 signaling pathway, PI3K-Akt signaling pathway, etc. The results of molecular docking confirmed that the core active components in BJJP could bind well to the key targets. Results from molecular dynamics simulation showed that the binding energies of AKT1-Luteolin, MMP9-quercetin, and MMP9-luteolin complexes were −28.93 kJ·mol−1, −37.12 kJ·mol−1, and −62.91 kJ·mol−1, respectively. Conclusion The study revealed that BJJP is characterized as multicomponent, multitarget, and multipathway to treat diabetic atherosclerosis, which is helpful to provide ideas and a basis for pharmacological research and clinical application in the future.