PatchDock Server Research Articles

In-silico designing of epitope-based vaccine against the seven banded grouper nervous necrosis virus affecting fish species.

Neural necrosis virus (NNV) of family Nodaviridae affect wide range of fish species with viral encephalopathy and retinopathy causing mass mortality up to 100%. Currently there is no effective treatment and depopulation is only suggested recommendation. New avenues and approach are required to control this harmful malady. In this study we developed an epitope-based vaccine (EBV), against NNV using computation approach. We have selected two conserved proteins RNA-dependent RNA polymerase (RdRP) and capsid proteins. Based on more than ~ 1000 epitopes we selected six antigenic epitopes. These were conjugated to adjuvant and linker peptides to generate a full-length vaccine candidate. Biochemical structural properties were analyzed by Phyre2 server. ProtParam, Molprobity. Ramachandran plot results indicate that 98.7% residues are in a favorable region and 93.4% residues in the favored region. The engineered EBV binds to toll like receptor-5 (TLR5) an important elicitor of immune response. Further molecular docking by PatchDock server reveals the atomic contact energy (i.e. − 267.08) for the best docked model of EBV and TLR5 receptor. The molecular simulation results suggest a stable interaction; the RMSD and RMSF values are 1–4 Ǻ and 1–12Ǻ, respectively. Further we have suggested the best possible codon optimized sequence for its cloning and subsequent purification of the protein. Overall, this is a first report to suggest an in-silico method for generation of an EBV candidate against NNV. We surmise that the method and approach suggested could be used as a promising cure for NNVs.

Molecular Docking Study of α-Cyclodextrin With Psoralen: MDA-MB-231 Cancer Cell

Psoralen is an important bioactive component, isolated from the leaves of Ficus carica (Fig). Psoralen is proved to inhibit breast cancer cell growth and in tumor bearing mice the function of osteoblasts and osteoclasts is regulated. It is difficult to treat Triple-Negative Breast Cancer, a sub type of breast cancer. On treating Fig leaf extract, it is found that the leaf extract inhibits the proliferation of MDA-MB-231, which is a TNBC cell line, but not MCF10A cells, which is normal breast epithelial cell line. To increase the stability, solubility, volatility, it is beneficial to encapsulate natural products with α-Cyclodextrin (α-CD). Cyclodextrin constituted by 6 glucose units are termed as α-Cyclodextrin. Compared to host molecule guest: host inclusion complexes exhibit improved chemical or biological properties. Main aim of the study is interaction of Psoralen with α-CD and MDA-MB-231 Cancer cell with α-CD: Psoralen inclusion complex by molecular docking studies. 3D structures of Psoralen, α-CD and MDA-MB-231 cancer cell are obtained and docking is carried out using PatchDock server. Model which is highly favorable will have a high score. Energetically favorable and most probable structures of α-CD: Psoralen and MDA-MB-231 cancer cell: α-CD Psoralen inclusion complex has a score of 1762 and 6230 respectively.

Molecular docking and density functional theory studies of potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles antifilarial compounds

The interaction of three potent antifilarial compounds (4C, 4F, and 3F) with filarial proteins thioredoxin, glutathione s-transferase and cyclophilin were investigated using molecular docking and density functional theory (DFT) studies. Molecular docking was performed using YASARA tool, Hex 8.0.0 Cuda tool and PatchDock server and docked complex were visualized by Discovery Studio 3.0. The predicted binding energy of antifilarial compounds 4C (−247.6, −243.8, −256.8 kcal mol−1), 4F (−242.6, −246.4, −232.4 kcal mol−1) and 3F (−272.4, −248.5, −277.7 kcal mol−1) with filarial protein 4FYU, 5D73, and 1A33, respectively. Docking results were strongly supported by molecular dynamics data and molecular mechanics-generalized born surface area (MM-GBSA) calculations. The optimized geometries of all three compounds were used for calculating the energies of the frontier molecular orbitals highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The lowest HOMO–LUMO energy gap in compound 3F suggested that it is the most bioactive molecule among all these three compounds, which is in accordance with the docking results of these compounds. The interaction energies between ligand and protein are mainly due to hydrogen bonds, hydrophobic interactions, and van der Waals interactions which give the stability to the complex. The structural information and docking studies of different filarial proteins with antifilarials obtained from this study could aid in screening and designing new antifilarial or selective inhibitors for chemotherapy against filariasis.

Differential binding of SARS-CoV-2 Spike protein variants to its cognate receptor hACE2 using molecular modeling based binding analysis.

The current emergence of novel coronavirus, SARS-CoV-2 and its ceaseless expansion worldwide has posed a global health emergency that has adversely affected the humans. With the entire world striving to understand the newly emerged virus, differences in morbidity and infection rate of SARS-CoV-2 have been observed across varied geographic areas, which have been ascribed to viral mutation and evolution over time. The homotrimeric Spike (S) glycoprotein on the viral envelope surface is responsible for binding, priming, and initiating infection in the host. Our phylogeny analysis of 1947 sequences of S proteins indicated there is a change in amino acid (aa) from aspartate (Group-A) to glycine (Group-B) at position 614, near the receptor- binding domain (RBD; aa positions 331-524). The two variants are reported to be in circulation, disproportionately across the world, with Group-A dominant in Asia and Group-B in North America. The trimeric, monomeric, and RBD of S protein of both the variant groups (A & B) were modeled using the Swiss-Model server and were docked with the human receptor angiotensin-converting enzyme 2 (hACE2) employing the PatchDock server and visualized in PyMol. Group-A S protein's RBD bound imperceptibly to the two binding clefts of the hACE2 protein, on the other hand, Group-B S protein's RBD perfectly interacted inside the binding clefts of hACE2, with higher number of hydrogen and hydrophobic interactions. This implies that the S protein's amino acid at position 614 near the core RBD influences its interaction with the cognate hACE2 receptor, which may induce its infectivity that should be explored further with molecular and biochemical studies.

Differential binding of SARS-CoV-2 Spike protein variants to its cognate receptor hACE2 using molecular modeling based binding analysising molecular modeling based binding analysis

The current emergence of novel coronavirus, SARS-CoV-2 and its ceaseless expansion worldwide has posed a global health emergency that has adversely affected the humans. With the entire world striving to understand the newly emerged virus, differences in morbidity and infection rate of SARS-CoV-2 have been observed across varied geographic areas, which have been ascribed to viral mutation and evolution over time. The homotrimeric Spike (S) glycoprotein on the viral envelope surface is responsible for binding, priming, and initiating infection in the host. Our phylogeny analysis of 1947 sequences of S proteins indicated there is a change in amino acid (aa) from aspartate (Group-A) to glycine (Group-B) at position 614, near the receptor- binding domain (RBD; aa positions 331-524). The two variants are reported to be in circulation, disproportionately across the world, with Group-A dominant in Asia and Group-B in North America. The trimeric, monomeric, and RBD of S protein of both the variant groups (A & B) were modeled using the Swiss-Model server and were docked with the human receptor angiotensin-converting enzyme 2 (hACE2) employing the PatchDock server and visualized in PyMol. Group-A S protein’s RBD bound imperceptibly to the two binding clefts of the hACE2 protein, on the other hand, Group-B S protein’s RBD perfectly interacted inside the binding clefts of hACE2, with higher number of hydrogen and hydrophobic interactions. This implies that the S protein’s amino acid at position 614 near the core RBD influences its interaction with the cognate hACE2 receptor, which may induce its infectivity that should be explored further with molecular and biochemical studies.

Anti-gout arthritic activities of Ethanolic and Aqueous leaf extracts of Cadaba fruticosa- An In vitro and In silico studies

In the present investigation an attempt was made to evaluate the in vitro and in silico anti-gout arthritic activity of ethanolic (EECF) and aqueous extracts (AECF) of leaves of Cadaba fruticosa. The in vitro anti-gout arthritic activity of EECF and AECF was evaluated in terms of their inhibitory potential of xanthine oxidase, proteinase enzymes as well as protein denaturation and membrane stabilization using standard protocols. For the analysis of in silico anti-gout arthritic activity, molecular docking was performed for the GC–Ms derived 15 phyto constituents using patch dock server to find a suitable antagonistic ligand for the enzymes cyclooxygenase I and matrix metalloproteinase IV since they are the key enzymes responsible for pain and degenerative changes. Among the EECF and AECF extracts the EECF extract exhibited higher inhibitory activity of the xanthine oxidase and proteinase enzyme. At the concentrations of 800 and 1000μg/ml the observed inhibitory activity was almost similar to the positive drug Allopurinol and Acetyl salicylic acid. Based on the docking score and activation energy the two phyto constituents Quercetin and Cadabicinediacetate inhibited the enzymes cyclooxygenase I and matrix metalloproteinase IV and serves as a better antagonistic ligand to suppress the pain and joint destruction. It may be concluded that the leaves of Cadaba fruticosa may further developed into a effective drug for the management of gouty arthritis due to its multi targeted inhibitory activity of several inflammatory mediators.

Repurposing of Drugs Targeted Against COVID-19 Spike Receptor for Treatment: An In silico Approach

An escalating pandemic by the novel SARS-CoV2 is spreading across the globe at a rate. An urgent need for therapy is needed. Initially, the virus appeared first in Wuhan, China, and later approximately in 187 countries worldwide. Coronaviruses are causative of respiratory as well as neurological diseases in humans. The novel zoonotic disease-causing coronaviruses are single-stranded RNA viruses. The coronavirus's outer structure consists of spike protein made up of glycoproteins, which binds to ACE (Angiotensin Converting Enzyme) protein when infected in humans. In the current study, 37 compounds that are already used in the biological field as anti-viral compounds are observed with bioinformatics tools. The repurposing drugs are docked against the spike receptor by molecular Docking. The ligand structure and the receptor structure are retrieved from Protein Data Bank. Patch dock server is an open freeware available for docking procedures. The results include acceleration and score of matched properties showing the feasibility of working the drug against SARS-nCoV. For the visualization of the final docked product, PyMOL and RasWin software’s are used. The scores of each ligand docked against the receptor show the compatibility working against the COVID-19 disease.

Effect of pH and structural orientation on supramolecular complexation of chloroquine in β-cyclodextrin medium

The supramolecular interaction of host-guest structure between Chloroquine (CQ) plus nano-hydrophobic cavity beta-cyclodextrin (β-CD) and the complex has observed by employing techniques such as UV and fluorescence spectroscopy. Here, the compound formed is of 1: 2 stoichiometric ratio. The chloroquine molecule has extremely caught into the cavity of β-cyclodextrin that is established by an in-depth analysis of spectral changes and matching to the absorption and fluorescence spectrometric interpretations. The binding constant for the inclusion complex at room temperature has evaluated by the use of Benesi-Hildebrand plot. The monocation and neutral forms of CQ with moist along with β-CD platform have discussed for the determination of pKa and pKa⁎. The thermal stability for the inclusion complex of CQ with β-CD has been examined by utilizing DSC technique. The change of the crystal arrangement of the substantial complex has substantiated by powder XRD technique. The mechanism of the inclusion complex and its orientation is done by utilizing Patch-Dock server. The cytotoxic exploration has again done to pure CQ along with its inclusion complex on MDA MB 231 cell line; then it is presented that the activity is subtle for the two materials.

Computational modeling of AGO-mediated molecular inhibition of ARF6 by miR-145

Inhibition of ADP-ribosylation factor 6 messenger RNA (ARF6 mRNA) by microRNA-145 (miR-145), mediated by Argonaute (AGO) protein, has been found to play essential roles in several types of cancer and cellular processes. This study aimed to model the molecular interaction between miR-145 and ARF6 mRNA with AGO protein. The sequences of miR-145 and the 3’ untranslated region (UTR) of ARF6 mRNA were retrieved from miRTarBase, followed by miRNA target-site and structure predictions were done using RNAhybrid, RNAfold, and simRNAweb, respectively. The interaction between the miRNA-mRNA duplex and AGO was further assessed via molecular docking, interaction analysis, and dynamics, using PatchDock Server, PLIP, and VMD/NAMD, respectively. The models between miR-145, predicted target site of ARF6 mRNA, and AGO protein returned stable thermodynamic variables with negative free energy. Specifically, the RNA duplex had an energy of -19.80 kcal/mol, while the docking had -84.58 atomic contact energy supported by 70 hydrogen bonds and 14 hydrophobic interactions. However, the stability of the RMSD plot was still unclear due to limited computational resources. Nevertheless, these results computationally confirm favorable interaction of the three molecules, which can be utilized for further transcriptomics-based drugs or treatments.

Enantioseparation of ketoconazole and miconazole by capillary electrophoresis and a study on their inclusion interactions with β-cyclodextrin and derivatives.

A chiral separation method coupled with capillary electrophoresis (CE) analysis for ketoconazole and miconazole enantiomers using chiral selectors such as β-cyclodextrin (β-CD) and hydroxypropyl-β-CD (HP-β-CD) was developed in this study, which included the optimisation, validation and application of the method on the antifungal cream samples. The formation of inclusion complex between the hosts (β-CD and HP-β-CD) and guests (ketoconazole and miconazole) were compared and analysed using ultraviolet-visible spectrophotometry, nuclear magnetic resonance (NMR) spectroscopy and molecular docking methods. Results from the study showed that in a concentration that ranged between 0.25 and 50 mg L-1 , the linear calibration curves of each enantiomer had a high coefficient of regression (R2 > 0.999), low limit of detection (0.075 mg L-1 ) and low limit of quantification (0.25 mg L-1 ). The relative standard deviation (RSD) of the intraday and interday analyses ranged from 0.79% to 8.01% and 3.30% to 11.43%, respectively, while the recoveries ranged from 82.0% to 105.7% (RSD < 7%, n = 3). The most probable structure of the inclusion complexes was proposed based on the findings from the molecular docking studies conducted using the PatchDock server.

In Silico Evaluation of Human Cathelicidin LL-37 as a Novel Therapeutic Inhibitor of Panton-Valentine Leukocidin Toxin of Methicillin-Resistant Staphylococcus aureus.

Incidence of drug resistance in clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) is attributed to its diverse repertoire of virulence factors. Of these virulence determinants, Panton-Valentine Leukocidin (PVL) has been experimentally validated as a prospective drug target due to its conspicuous and comprehensive role in nosocomial infections. This study encompassed an in silico approach to elucidate the antimicrobial potentiality of human cathelicidin LL-37 against PVL toxin of MRSA. Molecular docking studies of LL-37 and its segments with the PVL toxin subunits LukS and LukF were carried out using PatchDock server and the results were refined using FireDock server. The paramount ligand-receptor combination was selected and analyzed based on diverse parametric attributes and compared with the commercial inhibitors of PVL viz. Andrimid, Beclobrate, Beta-sitosterol, Diathymosulfone, and Probucol to determine the most potent inhibitor among them. Our results elucidated that the interaction of LL-37 with the LukS subunit of PVL toxin (minimum global energy of -61.82 kcal/mol) depicted 34 molecular interactions, while the commercial PVL inhibitors depicted fewer and insubstantial interactions. SWISS-ADME (Absorption, Distribution, Metabolism, and Excretion) and ToxinPred analysis of LL-37 further corroborated its null potency of toxicity in systemic milieu. The results obtained may credit this study as basis for the development of LL-37 as a potential inhibitor against virulent MRSA toxins, thereby exalting the treatment regimes for nosocomial infections in health care facilities worldwide.

Molecular Docking Studies of Podophyllotoxin and Its Derivatives against Metabolic Enzymes Regarding Anticancer Therapeutic Strategies

The objective of this study was to analyze the molecular characteristics of the podophyllotoxins and its derivatives with the metabolic enzymes and regulate the designing of therapeutic mechanism against malignant cells. One such inhibitor is podophyllotoxin with anticancer activity because of the capability to stop the metabolic enzymes. In this study, we undertook the in silico analysis with respect to molecular docking podophyllotoxin and its derivatives using the Patchdock server. Moreover, drug likeness of podophyllotoxin, etoposide, and teniposide was investigated using Lipinski filter and SwissADME. According to the molecular docking score, podophyllotoxin indicated that both derivatives (especially teniposide) showed a good binding affinity toward selected protein receptors.

Structure-Based Docking Studies of GLUT4 Towards Exploring Selected Phytochemicals from Solanum xanthocarpum as a Therapeutic Target for the Treatment of Cancer.

In recent years, there has been an exponential increase in the global burden of cancer which has been associated with several factors including environmental influence, aging, diet, infectious agents, hormonal imbalance and chronic inflammation, among others. Cancerous cells utilize more glucose for its proliferation and survival than normal cells. Thus, the regulation of glucose consumption of cancerous cells through the inhibition of glucose transporter-4-protein (GLUT4) encoded by solute carrier family-2-member-4-gene (Slc2a4) by selected phytochemicals from Solanum xanthocarpum may serve as a new therapeutic candidate for the treatment of cancer. The seven identified potential inhibitors of GLUT4 from Solanum xanthocarpum were retrieved from PubChem database. Examination of their drug-likeness, toxicity prediction and molecular docking studies of these compounds with GLUT4 were carried out using online tools such as Molinspiration, PreADMET V.2.0 and Patchdock server. The findings revealed that, five out of the seven compounds fulfil oral drugability of Lipinski's rule of five (RO5) while two slightly meet the criteria of RO5. Conversely, five of the compounds are predicted to be mutagen while the remaining two are predicted to be safe for the body. Additionally, stigmasterol glucoside has higher binding-affinity (7590) with GLUT4 when compared to doxorubicin (6600) the control. These findings suggest that stigmasterol glucoside from Solanum xanthocarpum could be a promising therapeutic agent with better therapeutic efficacy than doxorubicin in the treatment of cancer via the inhibition of GLUT4.

Molecular docking analysis of flavonoid compounds with HIV-1 Reverse transcriptase for the identification of potential effective inhibitors.

It is of interest to elucidate the binding mode analysis of 18 sulphonated flavones in the non nucleoside inhibitory binding pocket of the HIV-1 reverse transcriptase (PDB ID: 1RTD). We further compared them with the known Non Nucleosidic Reverse Transcriptase Inhibitors (NNRTI) drug molecules such as delaviridine, nevirapine and etravirine. Molecular docking studies of sulphonated flavones were performed in the binding pocket of reverse transcriptase using the PatchDock server. The flavones have different binding energies with RT and the atomic contact energy (ACE) value of sulfonated flavones range from-389 to-231 Kcal/mol while docking of the commercialized NNRTI showed the ACE value range from -486 to -224 Kcal/mol. This shows that most sulfonated flavones have ACE similar to the known NNRTI. Thus, seven compounds (FS-6, FS-7, FS-8, FS-9, FS-14, FS-15, FS-17) were reported as potent, selective, orally bio available, and nontoxic lead based on ADMET screening and effective binding analysis in the active site of the reverse transcriptase (PDB ID: 1RTD) for further consideration. We further document that compounds (FS-1, FS-10, FS-4 and FS-12) have unfavorable binding features to be considered as leads.

Spectral Studies on the Supramolecular Assembly of Uridine with β-Cyclodextrin and Its In Vitro Cytotoxicity

The supramolecular interaction between Uridine (UR) and β-cyclodextrin (β-CD) has been investigated in liquid, solid, and virtual state. Noncovalent interaction between UR and β-CD in aqueous medium was confirmed by using absorption, fluorescence emission, and time-resolved fluorescence spectroscopy. The solid inclusion complex was prepared using physical mixing, kneading method, and coprecipitation method and it was characterized using FT-IR, SEM, powder X-ray diffraction patterns TG/DSC, and 1H NMR techniques. The stoichiometric ratio of the inclusion complex was found to be 1:1 and the binding constant of the inclusion complex at 303 K were determined using Benesi–Hildebrand plot. The changed in the Gibbs free energy for the complexation reaction was determined and it was found that the complexation process was spontaneous. As the changes in the chemical shift, values of the UR have been observed after the formation of an inclusion complex. The inclusion process is virtually evident by molecular docking studies using the patch-dock server. As the biological application of this complexation, the cytotoxic activity has also been successfully tested against breast cancer cell line which exposed at different concentration for 74 h.

Molecular encapsulation of lidocaine and procaine into β-cyclodexrin cavity: in vitro cytotoxic evaluation

Among the potent anticancer agent, Local Anesthetics (LA) have been found to be efficient against many different types of cancer cell lines. However, the major disadvantage associated with the use of LA its low systemic bio-availability when administered due to its poor aqueous solubility. Our present work concentrates on improving the bio-availability by complexing with β-Cyclodextrin. We synthesized the inclusion complexes of selective LAs by co-precipitation method which is an efficient method among others and characterized the formulation of complex by UV, steady state and time resolved fluorescence studies. The optimization and orientation of the free LA and the complexes have also been studied by molecular docking with the help of Patch-Dock server. An in vitro study of cytotoxicity against breast cancer cell line is performed. Our study shows the formation of the complex with 1:1 ratio and the result showed that the improved CT activity for LDC:β-CD than the free LDC. For PRC and its complex with β-CD has no much activity even after forming a complex.

Antioxidant Activity and In Silico Analysis of Centella asiatica and Indigofera aspalathoides in Psoriasis

Psoriasis is a chronic inflammatory skin disorder, characterized by red thickened scaly patches with overlying silvery white scaly patches distributed into extensor surfaces involving palms and scalp. In the present study, we intended at assessing the antioxidant activity and interaction of bioactive compound present in ethanolic and ethyl acetate of Centella asiatica and Indigofera aspalathoides with (VEGF) vascular endothelial growth factor and inflammatory marker IL-17 in silico analysis, which in turn is an important factor for triggering the psoriasis. The whole plant active compounds extracted using ethanol, ethyl acetate. Extracts were screened for the presence of antioxidants by antioxidant scavenging activity- hydroxyl radical, superoxide anion radical, and nitric oxide radical and (1,1-Diphenyl-2-picrylhydrazyl) DPPH assay. In silico method, compound interactions with vascular endothelial growth factor (VEGF), interleukin-17 (IL-17) analysed using Patch Dock Server. MTT assay, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) performed in L929 fibroblasts cell line were used to evaluate the cell toxicity. Form our analysis, ethanolic extract of Indigofera aspalathoides extract (FSE) showed better antioxidant scavenging activity and compounds namely dodecanoic acid,10 methyl-,methyl ester and Pregnan-18-oic acid, 20-hydroxy-,[5alpha] has better affinity and produced docking score ­26.47 and -30.56 with vascular endothelial growth factor (VEGF), interleukin-17 (IL-17) as compared to control using in silico method. In case of cytotoxicity studies, 500μg/ml of ethanolic extract (FSE), Indigofera aspalathoides showed 85% of cell viability in L929 fibroblast.

Investigation of the interaction of allergens of Glycine max with IgE-antibody for designing of peptidomimetics based anti-allergen

Allergen induced IgE dependent type I hypersensitivity is the main cause of the allergy, which would be a burden on medical setup in coming years. Allergens of Glycine max have been isolated, and their disease relationships are documented. Therefore, it becomes important to investigate the interaction of different allergens of Glycine max with IgE and also screen suitable therapeutics to prevent this interaction. The amino acid sequences of all allergens of Glycine max and their isoallergens have been taken, and 3D structure of allergens (Gly m 3, Gly m 4, Gly m 5, Gly m 6 and Gly m 8) and their isoallergens were generated using Modeller v9.17. The modeled structures were further validated using PSVS, ProSA, RAMPAGE, and PDBsum. HL domain of Fab region of human IgE (PDBID: 2R56) was generated using UCSFchimera. The HL domain was minimized by Schrodinger software using the OPLS_2005 force field. SiteMap identified epitope binding site of the minimized domain. All the predicted epitopes of different allergens were docked to the binding site of HL domain using the Patchdock server. We have also designed a peptidomimetics based inhibitor targeted at interaction interface of Gly m8 and IgE, using in-silico virtual screening, molecular mechanics, and molecular dynamics simulation studies. These studies identified BDE32166344 ((N-(1-{[1-(1-aminocyclopentanecarbonyl)-3-hydroxypyrrolidin-3-yl]methyl}piperidin-4-yl)acetamide) as a peptidomimetics based lead with binding energy of −72.77 kcal/mol. Therefore, the present study investigates the interaction between different Gly m allergens and IgE antibody and identifies peptidomimetics based lead that might be developed as a suitable therapeutics against allergy caused by allergen of Glycine max.

Supramolecular Interaction of Primaquine with Native β-Cyclodextrin

The supramolecular host–guest inclusion complex of Primaquine (PQ) with the nano-hydrophobic cavity of beta-cyclodextrin (β-CD) was prepared by physical mixing, kneading and co-precipitation methods. The formation of an inclusion complex in PQ with β-CD in the solution phase has been confirmed by UV–visible and fluorescence spectroscopy. The stoichiometry of the inclusion complex is 1:1; the Primaquine molecule is deeply entrapped in the cavity of β-cyclodextrin, which was confirmed by analysis of spectral shifts and corresponding absorbance and fluorescence intensities. The Benesi–Hildebrand plot was used to calculate the binding constant of the inclusion complex of PQ with β-CD at room temperature. The Gibbs energy change of the inclusion complex process has been calculated. The $$ {\text{p}}K_{\text{a}} $$ and $$ {\text{p}}K_{\text{a}}^{*} $$ for the monocation and neutral equilibrium of PQ in aqueous and β-CD media are discussed. The thermal stability for the inclusion complex of PQ with β-CD has been analyzed using differential scanning calorimetry. The modification of the crystal structure to amorphous for the solid inclusion complex was confirmed by powder X-ray diffraction. The structure of the complex is proposed by docking studies using the Patch-Dock server. A cytotoxic analysis was also carried out for the pure PQ and its solid complex on the MDA MB 231 cell line and showed that the activity is good for both substances. The cytotoxicity neither improved nor decreased with the formation of the inclusion complex with β-CD.

Structural Characterization of Amyloid β17-42 Dimer by Potential of Mean Force Analysis: Insights from Molecular Dynamics Simulations.

Recent experiments with Amyloid β1-42 peptide have indicated that the initial dimerization of Aβ1-42 monomers to form amyloid dimers stand out as a key event in the generation of toxic oligomers. However, the structural characterization of Aβ1-42 dimer at the atomistic level and the dimerization mechanism by which Aβ1-42 peptides co-aggregate still remains not clear. In the present study, the process of Aβ17-42 peptide dimerization which is known to play an important role in the plaque formation in Alzheimer's disease was evaluated in terms of potential of mean force. The Aβ17-42 dimer was constructed using PatchDock server. We have used molecular dynamics (MD) simulation with the umbrella sampling methodology to compute the Potential of Mean Force for the dimerization of Aβ17-42. The global minima structure at the minimum distance of separation was isolated from the calculated free energy profile and the interactions involved in the formation of the dimer structure were examined. Protein-protein interfaces and the residueresidue interactions vital for generation of the dimer complexes were also evaluated. The simulation results elucidated the interaction between the monomeric units to be governed primarily by the hydrophobic and hydrogen bonds. The resultant Aβ17-42 dimer was found to have an increased β-strands propensity at the hydrophobic regions encompassing the CHC region. Furthermore, specific hydrophobic residues were found to play a vital role in the formation of the dimer complex. From the results we may therefore conclude hydrophobic region encompassing the CHC region to be crucial in dimerization process. The findings from this study provide detailed information for the complex process of early events of Aβ aggregation.