Exploration of the binding properties of the human serum albumin sites with neurology drugs by docking and molecular dynamics simulation

In this study, the binding properties of a set of neurology drugs to human serum albumin (HSA) were studied by docking and molecular dynamic (MD) methods. Based on the RMSD values for the MD simulation processes, the drug–protein complexes are stable. Site II of the HSA shows the best affinity for the studied drugs. Different kinds of interactions, including hydrogen bonding, π-cation interactions, and π–π interactions, are observable between ligand and protein during the MD simulation process. The MMGBSA calculations were done to evaluate the binding energy of the ligands and protein. The calculated energies are in good agreement with the previously reported experimental results. In some cases, there is a direct relation between the calculated binding energy with the half-life of the drugs, as it was expected.     

In Silico Molecular Docking Analysis of Karanjin against Alzheimer’s and Parkinson’s Diseases as a Potential Natural Lead Molecule for New Drug Design,Development and Therapy

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that have emerged as among the serious health problems of the 21st century. The medications currently available to treat AD and PD have limited efficacy and are associated with side effects. Natural products are one of the most vital and conservative sources of medicines for treating neurological problems. Karanjin is a furanoflavonoid, isolated mainly from Pongamia pinnata with several medicinal plants, and has been reported for numerous health benefits. However, the effect of karanjin on AD and PD has not yet been systematically investigated. To evaluate the neuroprotective effect of karanjin, extensive in silico studies starting with molecular docking against five putative targets for AD and four targets for PD were conducted. The findings were compared with three standard drugs using Auto Dock 4.1 and Molegro Virtual Docker software. Additionally, the physiochemical properties (Lipinski rule of five), drug-likeness and parameters including absorption, distribution, metabolism, elimination and toxicity (ADMET) profiles of karanjin were also studied. The molecular dynamics (MD) simulations were performed with two selective karanjin docking complexes to analyze the dynamic behaviors and binding free energy at 100 ns time scale. In addition, frontier molecular orbitals (FMOs) and density-functional theory (DFT) were also investigated from computational quantum mechanism perspectives using the Avogadro-ORCA 1.2.0 platform. Karanjin complies with all five of Lipinski’s drug-likeness rules with suitable ADMET profiles for therapeutic use. The docking scores (kcal/mol) showed comparatively higher potency against AD and PD associated targets than currently used standard drugs. Overall, the potential binding affinity from molecular docking, static thermodynamics feature from MD-simulation and other multiparametric drug-ability profiles suggest that karanjin could be considered as a suitable therapeutic lead for AD and PD treatment. Furthermore, the present results were strongly correlated with the earlier study on karanjin in an Alzheimer’s animal model. However, necessary in vivo studies, clinical trials, bioavailability, permeability and safe dose administration, etc. must be required to use karanjin as a potential drug against AD and PD treatment, where the in silico results are more helpful to accelerate the drug development.     

GC-MS,LC-MS/MS,Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.     

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer’s Disease

Background: Despite research on the molecular bases of Alzheimer’s disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. Methods: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. Results: Our results demonstrated the increased bioactivity of three plants’ metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. Conclusions: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.     

Spectroscopic and Molecular Docking Approaches for Investigation of Interaction of Phellopterin with Human Serum Albumin

The mechanism of interaction between human serum albumin (HSA) and natural product phellopterin (PL) from Angelica dahurica was investigated by spectroscopic techniques with molecular docking under simulated physiological conditions. The experimental results showed that the fluorescence of HSA was regularly quenched by PL, and the quenching constants (K_SV) decreased with increasing temperature, which indicated that the quenching mechanism was a static quenching procedure. The binding constants (K_A) were larger than 10^?5 M^?1 and the number of binding sites (n) was approximate to 1 at different temperatures, which indicated that the binding affinity was hige and there was just one main binding site in HSA for PL. According to thermodynamic parameters from Van't Hoff equation, the binding process of PL with HSA was spontaneous and exothermic process due to ΔG < 0, and the electrostatic force played major role in the binding between PL and HSA according to ΔH < 0 and ΔS > 0. The binding distance (r) was calculated to be about 3.35 nm, which implied that the energy transfer from HSA to PL occurred with high possibility according to the theory of Förster's non-radiation energy transfer. The microenvironment and conformation of HSA changed with the addition of PL based on the results of synchronous and three-dimensional fluorescence methods. The molecular docking analysis revealed the binding locus of PL to HSA in subdomain IIIA (Sudlow's site II).     

Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia

Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC₅₀ value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (K_D) value of 5.529 × 10⁻⁵ M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.     

An In Silico Investigation to Explore Anti-Cancer Potential of Foeniculum vulgare Mill. Phytoconstituents for the Management of Human Breast Cancer

Breast cancer is one of the most prevalent cancers in the world. Traditionally, medicinal plants have been used to cure various types of diseases and disorders. Based on a literature survey, the current study was undertaken to explore the anticancer potential of Foeniculum vulgare Mill. phytoconstituents against breast cancer target protein (PDB ID: 6CHZ) by the molecular docking technique. Molecular docking was done using Autodock/vina software. Toxicity was predicted by the Protox II server and drug likeness was predicted by Molinspiration. 100 ns MD simulation of the best protein-ligand complexes were done using the Amber 18 tool. The present molecular docking investigation has revealed that among the 40 selected phytoconstituents of F. vulgare, α-pinene and D-limonene showed best binding energy (−6 and −5.9 kcal/mol respectively) with the breast cancer target. α-Pinene and D-limonene followed all the parameters of toxicity, and 100 ns MD simulations of α-pinene and D-limonene complexes with 6CHZ were found to be stable. α-Pinene and D-limonene can be used as new therapeutic agents to cure breast cancer.     

Defining the Role of Isoeugenol from Ocimum tenuiflorum against Diabetes Mellitus-Linked Alzheimer’s Disease through Network Pharmacology and Computational Methods

The present study involves the integrated network pharmacology and phytoinformatics-based investigation of phytocompounds from Ocimum tenuiflorum against diabetes mellitus-linked Alzheimer’s disease. It aims to investigate the mechanism of the Ocimum tenuiflorum phytocompounds in the amelioration of diabetes mellitus-linked Alzheimer’s disease through network pharmacology, druglikeness and pharmacokinetics, molecular docking simulations, GO analysis, molecular dynamics simulations, and binding free energy analyses. A total of 14 predicted genes of the 26 orally bioactive compounds were identified. Among these 14 genes, GAPDH and AKT1 were the most significant. The network analysis revealed the AGE-RAGE signaling pathway to be a prominent pathway linked to GAPDH with 50.53% probability. Upon the molecular docking simulation with GAPDH, isoeugenol was found to possess the most significant binding affinity (−6.0 kcal/mol). The molecular dynamics simulation and binding free energy calculation results also predicted that isoeugenol forms a stable protein–ligand complex with GAPDH, where the phytocompound is predicted to chiefly use van der Waal’s binding energy (−159.277 kj/mol). On the basis of these results, it can be concluded that isoeugenol from Ocimum tenuiflorum could be taken for further in vitro and in vivo analysis, targeting GAPDH inhibition for the amelioration of diabetes mellitus-linked Alzheimer’s disease.     

The effects of single-walled carbon nanotubes (SWCNTs) on the structure and function of human serum albumin (HSA): Molecular docking and molecular dynamics simulation studies

Here, the interaction of single-walled carbon nanotubes (SWCNTs) and human serum albumin (HSA) as one of the most important proteins for carrying and binding of drugs was investigated and the impact of radius to volume ratio and chirality of the SWCNTs was evaluated using molecular docking method. Molecular docking results represented that zigzag SWCNT with radius to volume ratio equal to 6.77 × 10^?3 Å^?2 has the most negative binding energy (?17.16 kcal mol^?1) and binds to the HSA cleft by four π–cation interactions. To study the changes of HSA structure, the complex of HSA–SWCNT was subjected to 30 ns molecular dynamics simulation. The MD results showed that HSA was compressed about 2% after interaction with SWCNT. The equilibrated structure of HSA–SWCNT complex was used to compare the binding of warfarin to HSA in the absence and presence of SWCNT. The obtained results represent that warfarin-binding site was changed in the presence of SWCNT and its binding energy was increased. Really, warfarin was bound on the surface of SWCNT instead of its binding site on HSA. It means that HSA function as a carrier for warfarin is altered, the free concentration of warfarin is changed, and its release is decreased in the presence of SWCNT.     

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP’s). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser²⁶² residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer’s disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson’s disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of −6.9 kcal/mol forming interactions with binding pocket’s critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC₅₀ = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 10⁶ M⁻¹. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.     

Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer’s Disease Therapy

In over a century since its discovery, Alzheimer’s disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at BACE1 inhibition. Molecular docking, molecular dynamic (MD) simulations, and post-MD analyses are carried out on these selected compounds, which have been experimentally proven to exhibit allosteric inhibition on BACE1. The SwissDock software enabled us to identify more than five druggable pockets on the BACE1 structural surface using docking. Besides the active site region, a melatonin derivative (compound 1) previously proposed as a BACE1 allostery inhibitor showed appreciable stability at eight different subsites on BACE1. Refinement with molecular dynamic (MD) simulations shows that the identified non-catalytic sites are potential allostery sites for compound 1. The allostery and binding mechanism of the selected potent inhibitors show that the smaller the molecule, the easier the attachment to several enzyme regions. This finding hereby establishes that most of these selected compounds failed to exhibit strong allosteric binding with BACE1 except for compound 1. We hereby suggest that further studies and additional identification/validation of other BACE1 allosteric compounds be done. Furthermore, this additional allosteric site investigation will help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric BACE1 inhibitors.     

光谱-分子模拟法分析杨梅素与人血清白蛋白的分子作用机制

在模拟生理条件下,用多种光谱法结合分子对接法测定了杨梅素(MY)与人血清白蛋白(HSA)的相互作用.研究结果表明,MY能够明显猝灭HSA的荧光,MY与HSA的相互作用为复合式静态结合过程,结合强度较强.热力学和分子对接结果表明,MY与HSA是自发结合的,维持MY与HSA的相互作用力主要是氢键和范德华力.能量转移结果表明...     

De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study

In the present study, pharmacoinformatics paradigms include receptor-based de novo design, virtual screening through molecular docking and molecular dynamics (MD) simulation are implemented to identify novel and promising HIV-1 integrase inhibitors. The de novodrug/ligand/molecule design is a powerful and effective approach to design a large number of novel and structurally diverse compounds with the required pharmacological profiles. A crystal structure of HIV-1 integrase bound with standard inhibitor BI-224436 is used and a set of 80,000 compounds through the de novo approach in LigBuilder is designed. Initially, a number of criteria including molecular docking, in-silico toxicity and pharmacokinetics profile assessments are implied to reduce the chemical space. Finally, four de novo designed molecules are proposed as potential HIV-1 integrase inhibitors based on comparative analyses. Notably, strong binding interactions have been identified between a few newly identified catalytic amino acid residues and proposed HIV-1 integrase inhibitors. For evaluation of the dynamic stability of the protein-ligand complexes, a number of parameters are explored from the 100 ns MD simulation study. The MD simulation study suggested that proposed molecules efficiently retained their molecular interaction and structural integrity inside the HIV-1 integrase. The binding free energy is calculated through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach for all complexes and it also explains their thermodynamic stability. Hence, proposed molecules through de novo design might be critical to inhibiting the HIV-1 integrase.     

Studies of the Interaction Between Ronidazole and Human Serum Albumin by Spectroscopic and Molecular Docking Methods

Ronidazole (RNZ) is widely used for the therapeutic treatment of farmed animals and is suspected of being a human carcinogen and mutagen. The interaction between RNZ and human serum albumin (HSA) was investigated systematically by fluorescence spectroscopy, synchronous fluorescence, three-dimensional fluorescence, CD spectroscopy, UV–vis absorption spectroscopy and a molecular docking study. The results indicate that the probable quenching mechanism of HSA by RNZ is dynamic quenching. The corresponding thermodynamic parameters, such as ΔH, ΔS and ΔG, etc., were calculated according to the van’t Hoff equation. The results indicate that the forces acting between RNZ and HSA are mainly hydrogen bonds and van der Waals forces. The conformational changes in the interaction were studied by synchronous fluorescence, CD spectroscopy and three-dimensional fluorescence spectra. The results reveal that the microenvironment and conformation of HSA has been changed. A molecular modeling study further confirmed the binding mode obtained by the experimental studies.     

A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic,Biochemical, and Molecular Modeling Approaches

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy.     

Cavities create a potential back door in epoxide hydrolase Rv1938 from Mycobacterium tuberculosis—A molecular dynamics simulation study

Mycobacterium tuberculosis (Mtb) is the causative organism of tuberculosis. Extensively drug resistant strains and latency have posed formidable challenges in the treatment of tuberculosis. The current study addresses an alpha/beta hydrolase fold bearing enzyme, epoxide hydrolase Rv1938 from Mtb. Epoxide hydrolases are involved in detoxification processes, catabolism and regulation of signaling molecules. Using GROMACS, a 100 ns Molecular Dynamics (MD) simulation was performed for Rv1938. Cavities were identified within the protein at various time frames of the simulation and their volumes were computed. During MD simulation, in addition to the substrate binding cavity, opening of two new cavities located behind the active site was observed. These cavities may be similar to the backdoor proposed for acetylcholinesterase. Structural superimposition of epoxide hydrolase from Mtb with the epoxide hydrolase of Agrobacterium radiobacter1 AD1 (Ephy) indicates that cavity1 in Mtb lies at an identical position to that of the water tunnel in Ephy. Further, docking of the substrate and an inhibitor with protein structures obtained from MD simulation at various time frames was also performed. The potential role of these cavities is discussed.     

Characterization of the interaction between a platinum(II) complex and human serum albumin: spectroscopic analysis and molecular docking

In this study, the interaction between (2,2?-bipyridine)(pyrrolidinedithiocarbamato) platinum(II) nitrate, [Pt(bpy)(pyr-dtc]NO₃, and human serum albumin (HSA) was investigated by various spectroscopic methods (UV–vis, fluorescence, CD and FT-IR) and molecular docking technique at three temperatures. UV–vis absorption spectroscopy showed that Pt(II) complex can denature the protein at moderate concentrations. The results of emission quenching at two temperatures has revealed that the quenching mechanism of Pt(II) complex with HSA was static quenching mechanism. Binding constants (K), binding site number (n) and corresponding thermodynamic parameters ?G?, ?H? and ?S? were calculated and revealed that hydrophobic forces played a major role when Pt(II) complex interacted with HSA. The binding distance (r) between above complex and HSA based on Förster?s theory of non-radiation energy transfer was calculated as 3.22 nm. Alterations of HSA secondary structure induced by complex were confirmed by FT-IR and CD measurements. Also, a molecular docking study was performed for identification of key structural features of binding of the Pt complex into the receptor and predicting bioactive conformers. Our results may provide valuable information to understand the mechanistic pathway of drug delivery and to pharmacological behavior of drug.     

Inhibitory Activity and Mechanism Investigation of Hypericin as a Novel α-Glucosidase Inhibitor

α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC₅₀) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10⁻⁵ M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.     

Revealing the ionization ability of binding site I of human serum albumin using 2-(2'-hydroxyphenyl)benzoxazole as a pH sensitive probe

The ability of site I of human serum albumin (HSA) to bind medium sized molecules is important for the distribution, metabolism, and efficacy of many drugs. Herein, we show that this binding site has the ionization ability that may alter the drug structure during the process of its delivery. We reveal this ability by employing 2-(2'-hydroxyphenyl)benzoxazole (HBO) as a pH sensitive probe. Binding of HBO in site I is studied here at physiological pH 7.2 using steady-state and lifetime spectroscopic measurements, molecular docking and molecular dynamics (MD) simulation methods. The complex photophysics of HBO and the unique fluorescence signature of its anionic form indicate that, upon binding with HSA, the molecule exists in equilibrium between the anionic and the syn-keto forms. The position of HBO inside the binding site was determined experimentally by measuring the fluorescence quenching of W214, the sole tryptophan residue in HSA. The ionization degree of HBO inside the binding site was estimated to be close to the ionization degree of HBO in an aqueous solution of pH 10. This was concluded by comparing the fluorescence behavior of bound HBO to that of HBO in different solvents and in aqueous solutions of different pH values. Molecular docking and MD simulations show that HBO binds in site I close to W214, confirming the experimental results, and pinpoint the dominant role of hydrophobic interactions in the binding site. The formation of the anionic form is proposed to be due to through-space interaction between the OH group of HBO and both R222 and I290 with a binding mode similar to that of warfarin in site I. Comparison of the results with those of HBO mixed with key amino acids in solution indicates the importance of through-space interaction in the formation of the anion, similar to enzymatic reactions.     

Structural bioinformatics-based identification of putative plant based lead compounds for Alzheimer Disease Therapy

Plant based lead compounds have been historically incredible as a source of therapeutic agents for various complex disorders including Alzheimer’s disease (AD). AD is one of the leading neurodegenerative disorder in which the underlying risk factors remain largely unclear and presently, there is no disease modifying treatment available. Despite its potential, to date only few compounds have entered for clinical trials. Herein, we described the identification of plant based lead compounds for treatment of AD through an integrative approach of pharmacokinetics and structure bioinformatics approach. In particular we performed screening of lead compounds from 3 traditional medicinal plants namely Withania somnifera, Bacopa monnieri and Morus alba, which are known to have potential for treatment of neurodegenerative disease. We retrieved a total of 210 plant based compounds of which 21 compounds were screened based on their pharmacokinetic properties. Further, Docking study against 7 known AD associated targets were carried out to identify the binding sites and direct interacting residues. In addition we investigate the stable and reliable binding mechanism of top such plant compounds against 3 targets through molecular docking followed by Molecular Dynamic(MD) simulation. The results obtained in the study revealed that 3 drug compounds namely Morusin (MRSN), Withanone (WTHN) and 27-Hydroxywithanolide B (HWTHN) were identified as putative lead compounds against mono amine oxidase (MAOB), Beta-secretase 1(BACE1) and phosphodiesterase 4D.