Identification of potential phytochemical inhibitors for the proven six chronic obstructive pulmonary disease biomarkers - A molecular dynamics study.

COPD is a multifactorial lung disease causing breathing difficulties in individuals and is becoming a major health concern worldwide. The unclear pathogenic mechanism and high mortality rate urge the development of drugs against this disease. In this study, around six COPD biomarkers identified from the preceding research through integrated gene expression analysis were taken as COPD target proteins. A total of 3307 phytocompounds were included in the COPD phytocompound library from 59 therapeutic plant sources. Furthermore, a crucial three-step virtual screening process (Absorption, Distribution, Metabolism, and Excretion, respiratory nontoxicity, less harmful and nontoxic compound category) was implemented to filter the potential drug-like phytocompounds. As a result, 160 phytocompounds were filtered with desired Absorption, Distribution, Metabolism, Excretion and Toxicity properties. The filtered 160 phytocompounds were docked against six COPD target proteins and the best-docked complexes were identified through visual inspection based on six unique parameters in SeeSAR. Furthermore, the best docked complexes were subjected to molecular dynamics simulation studies to assess the stability and conformational changes of the complexes. The presence of few amino acid residues within the crucial active, allosteric and catalytic sites of the six target proteins were revealed from the binding interaction types and major residual fluctuations from molecular docking and dynamic simulation studies respectively. This is indicative of the potential inhibitory activity of phytocompounds against the COPD biomarkers. Here we report the identified phytocompounds as a promising lead molecule for the six COPD biomarkers through in silico analysis opening new avenues in COPD pathogenesis and treatments.Communicated by Ramaswamy H. Sarma.

Design, Synthesis, and Molecular Docking Studies of Curcumin Hybrid Conjugates as Potential Therapeutics for Breast Cancer.

Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named CMC1-6. These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with CMC1 and CMC2 significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs.

Synergistic Effects of Limosilactobacillus fermentum ASBT-2 with Oxyresveratrol Isolated from Coconut Shell Waste.

Value-added phytochemicals from food by-products and waste materials have gained much interest and among them, dietary polyphenolic compounds with potential biological properties extend a promising sustainable approach. Oxyresveratrol (Oxy), a stilbenoid polyphenol, possesses great therapeutic potential, though its pharmacokinetic issues need attention. A good source of oxyresveratrol was found in underutilized coconut shells and the synbiotic applications of the compound in combination with a potential probiotic isolate Limosilactobacillus fermentum ASBT-2 was investigated. The compound showed lower inhibitory effects on the strain with minimum inhibitory concentration (MIC) of 1000 µg/mL. Oxyresveratrol at sub-MIC concentrations (500 µg/mL and 250 µg/mL) enhanced the probiotic properties without exerting any inhibitory effects on the strain. The combination at sub- MIC concentration of the compound inhibited Salmonella enterica and in silico approaches were employed to elucidate the possible mode of action of oxy on the pathogen. Thus, the combination could target pathogens in the gut without exerting negative impacts on growth of beneficial strains. This approach could be a novel perspective to address the poor pharmacokinetic properties of the compound.

Biological processes and key druggable targets involved in age-associated memory loss: A systematic review.

Age-associated memory loss is highly prevalent in the elder population. The inception of neurodegenerative diseases acts as a causative factor for the onset of memory loss in aged individuals. The pathophysiological mechanisms of memory loss associated with the onset of neurodegenerative diseases and normal aging processes share certain similarities as well as differences. The normal age-associated memory loss is attributed to the impairment of calcium metabolism, dysregulated cholesterol metabolism, the prevalence of oxidative stress, inappropriate functioning of hormones as well as genetic factors. Vital information regarding the key biological processes and the druggable targets involved in the onset of memory loss in the elder population has been provided in this article. The genomic and proteomic profiles of key druggable targets retrieved from the experimental evidence, co-expression studies and databases are also presented in this article. The genomic and proteomic information of druggable targets will aid in the identification of therapeutic agents which could effectively regulate the key biological processes involved in the age-associated memory loss.

In-silico driven design and development of spirobenzimidazo-quinazolines as potential DNA gyrase inhibitors.

DNA gyrase and Topoisomerase IV are promising antibacterial drug targets as they regulate bacterial DNA replication and topology. In a quest for novel DNA topoisomerase inhibitors, a multidisciplinary approach was adopted that involves computational prediction of binding sites and molecular modelling followed by green synthesis and biological evaluation of antibacterial activity of spirobenzimidazo quinazolines derivatives. Using basic quantum chemistry principles, we evaluated spirobenzimidazo quinazolines derivatives with their pharmacokinetic profiles. Based on the results of the aforesaid in-silico studies, we synthesized a series of titled compounds using green synthetic methodology that were validated as potential antimicrobial agents. Quantum chemoinformatics based predicted activity for the synthesized compounds 9b, 9c, and 9j was concomitant with biological evaluation of broadspectrum antibacterial activity. Biological evaluation revealed that inhibition of biofilm formation was due to their potential antibacterial activity. We believe that the novel spirobenzimidazo quinazolines have the potential to be alternatives to aminocoumarins and classical quinazolines upon detailed target specific biological studies.

Expansion of Phosphane Treasure Box for Staudinger Peptide Ligation.

A smooth traceless ligation strategy using an air-stable phosphane probe (2-(diphenylphosphanyl)phenyl)methanol as a C-terminus activator has been demonstrated at simple and sterically hindered amino acid junctions (Gly, Ala, Trp, Glu). This Staudinger peptide ligation proceeds via formation of a seven-membered transition state to afford di-, tetra-, and pentapeptides in 78-95% yields. The experimental results of ligation at Gly junction and regioselective ligation at Glu junction were theoretically studied by computational calculations. These findings established the versatile behavior of our synthesized phosphane probe for Staudinger peptide ligation toward synthesizing peptides and proteins of choice.

Review on druggable targets of key age-associated properties regulated by therapeutic agents.

Aging is a biological process which accounts for the deterioration of effective physiological functions. The malfunctioning of vital organ systems leads to the onset of neurodegenerative, cardiovascular, and immunomodulatory diseases in the elder population. Age-dependent mitochondrial dysfunctions trigger the production of reactive oxygen species, which serve as a major contributing factor for the onset of age-associated diseases. The increasing burden of age-related pathologies explicates the relevance of identifying novel therapeutic agents with enhanced potency and bioavailability. Key information on the biological mechanisms of significant age-related diseases aids in understanding relevant druggable targets essential for the initiation and progression of the disease. This review provides detailed insights into the druggable targets of key anti-aging properties of therapeutic agents such as anti-oxidant, immunomodulation, cardioprotection, anti-melanogenic, and anti-elastase properties. This information aids in the development of novel therapeutic agents/ supplements with enhanced efficacy.

Computational strategies towards developing novel antimelanogenic agents.

AIMS: Extrinsic ageing or photoageing relates to the onset of age-linked phenotypes such as skin hyperpigmentation due to UV exposure. UV induced upregulated production of tyrosinase enzyme, which catalyses the vital biochemical reactions of melanin synthesis is responsible for the inception of skin hyperpigmentation. We aimed to generate a validated QSAR model with a dataset consisting of 69 thio-semicarbazone derivatives to elucidate the physicochemical properties of compounds essential for tyrosinase inhibition and to identify novel lead molecules with enhanced tyrosinase inhibitory activity and bioavailability. MAIN METHODS: Lead optimization and insilico approaches were employed in this research work. QSAR model was generated and validated by exploiting Multiple Linear Regression method. Prioritization of lead-like compounds was accomplished by performing multi parameter optimization depleting molecular docking, bioavailability assessments and toxicity prediction for 69 compounds Derivatives of best lead compound were retrieved from chemical spaces. KEY FINDINGS: Molecular descriptors explicated the significance of chemical properties essential for chelation of copper ions present in the active site of tyrosinase protein target. Further, derivatives which comprise of electron donating groups in their chemical structure were predicted and analysed for tyrosinase inhibitory activity by employing insilico methodologies including chemical space exploration. SIGNIFICANCE: Our research work resulted in the generation of a validated QSAR model with higher degree of external predictive ability and significance to tyrosinase inhibitory activity. We propose 11 novel derivative compounds with enhanced tyrosinase inhibitory activity and bioavailability.

Aziridine based electrophilic handle for aspartic acid ligation.

A one-pot ligation strategy at aspartic acid junctions has been developed by successfully incorporating aziridin-2,3-dicarboxylate to the N-side of a peptide fragment, affording N-aziridine appended peptides, which were ligated in solution phase with a variety of small peptide thio acids to afford native peptides, following a ring-opening/peptidyl migration/desulfurization strategy. The reaction proceeds in a highly regiospecific manner, and provides short native peptides in good isolable yields. A variety of aspartame based peptides were synthesized to showcase the generality of this aziridine based ligation. Computational studies have also been performed to obtain insight about the reaction pathway.

Design and discovery of novel monastrol-1,3,5-triazines as potent anti-breast cancer agent via attenuating Epidermal Growth Factor Receptor tyrosine kinase.

A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via one-pot synthesis using Bi(NO3)3 as a catalyst. Entire compounds were evaluated for their anticancer activity against HeLa (cervical cancer), MCF-7 (breast cancer), HL-60 (Human promyelocytic leukemia), HepG2 (Hepatocellular carcinoma) and MCF 12A (normal epithelial breast cell line) using MTT assay, where they showed highest inhibitory activity against MCF-7. The molecules were also found to be non-toxic to MCF 12A cells. These molecules showed considerable inhibitory percentage against Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK), in in-vitro assay. Molecular docking study was carried out on the analogs and reference compound (Erlotinib) into the ATP binding site of EGFR-TK domain (PDB ID:1M17) to elucidate vital structural residues necessary for bioactivity. The effect of most active compound 7l was also estimated in-vivo in DMBA induced mammary tumor in female Sprague-Dawley rats. The effect of anti-breast cancer effect of 7l was quantified on the basis of tumour incidence, body weight and tumor volume in DMBA-induced rats. Its effect on biochemical parameters, such as antioxidant status (SOD, CAT, GPX and GSH) and lipid peroxidation was also studied. The compound 7l showed inhibition of EGFR downstream signalling in the western blot analysis.

Traceless reductive ligation at a tryptophan site: a facile access to ß-hydroxytryptophan appended peptides.

An efficient methodology for cysteine-free ligation at a tryptophan (Trp) site is described. A chemically active scaffold, ß-hydroxy-α-azidotryptophan, has been synthesized and explored towards the synthesis of a series of ß-hydroxytryptophan appended native peptides in good yields via one-pot reductive traceless ligation of ß-O-peptidyl-α-azidotryptophan involving an O → N peptidyl transfer strategy. Pre-organized conformational analysis and reaction energy pathway based theoretical studies further supported the experimental findings on the chemical structure stability of ligated products.

Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents.

GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (α1ß3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis,trans-isomers were isolated from commercially available 2,6-dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 µM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 µM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > > cis,trans-isomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the ß3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis > trans,trans > cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices.

Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation. OBJECTIVE: The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space. METHOD: We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. RESULTS: The robustness of the model is demonstrated by its statistical validation (Ntraining = 111, R2 = 0.85, Q2lmo = 0.84) and by the prediction of HIV-1 inhibition activity for experimentally measured compounds. CONCLUSION: Finally, 5 novel hit compounds were designed in silico by using a virtual screening approach. The new hits met all the pharmacophore constraints and predicted pIC50 values within the binding ability of HIV-1 RT protein targets.

Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies.

Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.

Synthesis, bioassay, and QSAR study of bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles.

A statistically significant QSAR model describing the bioactivity of bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles (N = 41, n = 8, R(2) = 0.824, R(2)cv = 0.724, F = 18.749, s(2) = 0.0018) was obtained employing CODESSA-Pro software. The bronchodilatory active 4H-pyrano[3,2-c]pyridine-3-carbonitriles 17-57 were synthesized through a facile approach via reaction of 1-alkyl-4-piperidones 1-4 with ylidenemalononitriles 5-16 in methanol in the presence of sodium. The bronchodilation properties of 17-57 were investigated in vitro using isolated guinea pig tracheal rings pre-contracted with histamine (standard method) and compared with theophylline (standard reference). Most of the compounds synthesized exhibit promising bronchodilation properties especially, compounds 25 and 28.

Synthesis, and QSAR analysis of anti-oncological active spiro-alkaloids.

QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software. The dispiro[3H-indole-3,2'-pyrrolidine-3',3"-piperidines] 24-48 were synthesized via [3 + 2]-cycloaddition reaction of azomethine ylides, (generated in situ via decarboxylative condensation of isatins 21-23 with sarcosine) and 3E,5E-1-alkyl-3,5-bis(arylmethylidene)-4-piperidones 10-20. Some of the synthesized analogues exhibited promising antitumor properties against HELA (cervical), HEPG2 (liver), T-47D, MCF7 (breast), and HCT116 (colon) human tumor cell lines, demonstrating activity close to or even better than the standard Doxorubicin, based on in vitro Sulfo-Rhodamine-B bio-assay.

Theoretical modeling of HPV: QSAR and novodesign with fragment approach.

Structure-activity relationships in a data set of HPV6-E1 helicase ATPase inhibitors were investigated based on two different sets of descriptors. Statistically significant four parameter Quantitative Structure-Activity Relationships (QSAR) models were constructed and validated in both cases (R(2)=0.849; R(2) cv=0.811; F=52.20; s(2)=0.25; N=42). A Fragment based QSAR (FQSAR) approach was applied for developing a fragment-QSAR equation, which enabled the construction of virtual structures for novel ATPase inhibitors with desired or pre-defined activity.

Synthesis of L-Lys-Aminoxy-Goralatide.

Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported to be rather unstable in solution (half-life 4.5 min). In this work, we report the synthesis of an aminoxy analog of Goralatide. Aminoxy moiety is expected to provide increased stability and bioavailability of the Goralatide analog.

In silico machine learning methods in drug development.

Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases.

Long-range chemical ligation from N→N acyl migrations in tryptophan peptides via cyclic transition states of 10- to 18-members.

Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.