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Lignin peroxidase is a heme-containing biocatalyst, well-known for its diverse applications in the fields from environmental chemistry to biotechnology. LiP-mediated oxidative catalysis is H2O2-dependent, and can oxidize phenolic, and non-phenolic substrates by oxidative cleavage of the C–C and C–O bonds of lignin. In contrast to fungi-derived LiP, the binding affinity of bacterial-derived LiP to lignin at the molecular level is poorly known to date. Tremendous wet-lab studies have been unveiled that provide degradation and biotransformation information on kraft lignin, whilst studies on the completely transformed compounds and the degradation of each transformed compounds simultaneously during degradation are scarce. To gain an understanding of the degradation process using docking, and MDS based studies, we assessed the binding affinity of selected lignin model compounds with bacterial origin LiP and validated such docked complexes exploiting 30 ns molecular dynamics simulations. We selected and picked a total of 12 lignin model compounds for molecular modeling analysis, namely two chlorinated lignin model compounds (monomer) (2-chlorosyringaldehyde and 5-chlorovanillin), eight standard lignin model compounds (veratryl alcohol, syringyl alcohol, sinapyl alcohol, methyl hydroquinone, guaiacol, coniferyl alcohol, catechol, and 4-methoxy phenol), while, two 4-O-5, and β-O-4 linkage-based multimeric model compounds (dimer: 2-methoxy-6-(2-methoxy-4-methylphenoxy)-4-methylphenol; trimer: syringyl β-O-4 syringyl β-O-4 sinapyl alcohol). Far more specific binding residues were observed from XP-Glide docking, as TYR, HIP (protonated histidine), PHE, VAL, ASP, THR, LYS and GLN. The binding affinity was confirmed by the Gibbs free energy or binding energy (ΔG) score; furthermore, it is found that the maximum binding energy seems to be observed for 4-methoxyphenol with a Glide score of −3.438 with Pi–Pi stacking and H-bond type bonding interactions, whilst the lowest XP Gscore as −8.136 with Pi–Pi stacking and H-bond (side chain) type bonding interactions were found for the trimer model compound. The docked complexes were further evaluated for deep rigorous structural and functional fluctuation analyses through high-performance molecular dynamics simulations-DESMOND, after a post simulation run of 30 ns. The RMSD trajectory analyses of the protein-ligands were found to be in the equilibrium state at the end of simulation run for multimeric lignin model compounds. In addition, ionic ligand–protein interaction occurs among chlorinated compounds, while hydrophobic and H-bond contacts have frequently been observed in all lignin-model compounds. The findings herein demonstrate that bacterial LiP can effectively catalyze multiple lignin model compounds, and it might further be used as an effective tool for sustainable mitigation of diverse environmental contaminants.

An endless drug-resistant strains of Helicobacter pylori and multitudinous drug reactions are obstacles in the treatment of H. pylori infections, thereby ambitious novel proof-of-concept for inhibi...

INTRODUCTION: Treatment failures of standard regimens and new strains egression are due to the augmented drug resistance conundrum. These confounding factors now became the drug designers spotlight to implement therapeutics against Helicobacter pylori strains and to safeguard infected victims with devoid of adverse drug reactions. Thereby, to navigate the chemical space for medicine, paramount vital drug target opting considerations should be imperative. The study is therefore aimed to develop potent therapeutic variants against an insightful extrapolative, common target LpxC as a follow-up to previous studies. METHODS: We explored the relationships between existing inhibitors and novel leads at the scaffold level in an appropriate conformational plasticity for lead-optimization campaign. Hierarchical-clustering and shape-based screening against an in-house library of > 21 million compounds resulted in panel of 11,000 compounds. Rigid-receptor docking through virtual screening cascade, quantum-polarized-ligand, induced-fit dockings, post-docking processes and system stability assessments were performed. RESULTS: After docking experiments, an enrichment performance unveiled seven ranked actives better binding efficiencies with Zinc-binding potency than substrate and in-actives (decoy-set) with ROC (1.0) and area under accumulation curve (0.90) metrics. Physics-based membrane permeability accompanied ADME/T predictions and long-range dynamic simulations of 250 ns chemical time have depicted good passive diffusion with no toxicity of leads and sustained consistency of lead1-LpxC in the physiological milieu respectively. CONCLUSIONS: In the study, as these static outcomes obtained from this approach competed with the substrate and existing ligands in binding affinity estimations as well as positively correlated from different aspects of predictions, which could facilitate promiscuous new chemical entities against H. pylori. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-019-00572-5) contains supplementary material, which is available to authorized users.

Mycobacterium tuberculosis is the bacteria that cause tuberculosis (TB), an infection that usually affects the lungs and can be fatal without proper treatment. Combating through available drugs became a difficult task due to drug resistance and lack of appropriate common targets against genetically diverse strains. Since to improve efficacy, the effective targets should be identified and critically assessed. In the study, we aim to predict the potential novel targets against M. tuberculosis strains by employing in silico approach. The complete proteomic datasets of 23 M. tuberculosis strains was comparatively processed by executing R-scripts and eventually predicted 3906 'conserved gene products'. Further, we performed subtractive proteomic approach in search of promising crucial targets. Consequently, eight enzymes and two membrane proteins were prioritized as new therapeutic and vaccine targets respectively which found to have more interactors in network with high-confidence score, druggability and antigenicity. Therefore, outcomes of the study emphasize the importance of new targets may counteract with false-positive/negatives and facilitate appropriate potential targets for a new insight of reliable therapeutic development. Key words: Mycobacterium tuberculosis, Multidrug resistance tuberculosis and Extensive drug resistant tuberculosis.

The study deals with structure-based rational drug design against the chief zinc-rely endopeptidase called matrilysin (MMP-7) that is involved in inflammatory and metastasis process of several carcinomas. Hyperactivated matrilysin of human was targeted, because of its hydrolytic actions on extracellular matrix (ECM) protein components constitutes fibrillar collagens, gelatins, fibronectins and it also activates zymogen forms of vital matrix metalloproteinases (gelatinase A-MMP-2 and B-MMP-9) responsible for ECM destruction in many cancers. In the present work, e-pharmacophores were generated for the respective five co-crystal structures of human matrilysin by mapping ligand’s pharmacophoric features. During the lead-optimization campaign, the five e-pharmacophores-based shape screening against an in-house library of >21 million compounds created a dataset of 5000 structural analogs. The subsequent three different docking strategies, including rigid-receptor docking, quantum-polarized-ligand docking, induced-fit docking and free energy binding calculations resulted four leads as novel and potent MMP-7 binders. These four leads were observed with good pharmacological features and good receiver operating characteristics curve metrics (ROC: 0.93) in post-docking evaluations against five existing co-crystal inhibitors and 1000 decoy molecules with MMP-7. Moreover, stability and dynamics behavior of matrilysin-lead1 complex and matrilysin-cocrystal ligand (TQJ) complex were analyzed in natural physiological milieu of 1000 ns or 1 µs molecular dynamics simulations. Lead1-MMP-7 complex was found with an average Cα root-mean-square deviation (RMSD) of 2.35 Å, average ligand root-mean-square fluctuations (RMSF) of 0.66 Å and the strong metallic interactions with E220, a key residue for proteolytic action thereby hinders ECM proteolysis that in turn can halt metastatic cancerous condition. Communicated by Ramaswamy H. Sarma

The developing potent vaccine is a pre-emptive strategy to tackle drug abuses and maladies of multidrug-resistant Helicobacter pylori strains. Ongoing vaccine studies are being conducted, however, ...

Gastric cancer risk and adverse ramifications by augmented multi-drug resistance (MDR) of Helicobacter pylori are alarming serious health concern. Combating through available drugs is a difficult task due to lack of appropriate common targets against genetically diverse strains. To improve efficacy, the effective targets should be identified and critically assessed. In the present study, we aim to predict the potential novel targets against H. pylori strains by employing computer aided approach. The genomic dataset of 53 H. pylori strains was comparatively processed and eventually predicted 826 'conserved gene products'. Further, we performed subtractive genomic approach in search of promising crucial targets through the combination of in silico analyses. Codon adaptation index (CAI) value calculation and literature surveys were also done in order to find highly expressed gene products with novelty. Consequently, four enzymes and three membrane proteins were prioritized as new therapeutic and vaccine targets respectively which found to have more interactors in network with high-confidence score, druggability, antigenicity and molecular weight110 kDa. Therefore, our results underpin the importance of new targets may counteract with false-positive/negatives and facilitate appropriate potential targets for a new insight of reliable therapeutic development.

The cascade of complications by Helicobacter pylori including extra-gastric and peptic ulcers to gastric cancer imposes a salient cause of cancer death globally. Adverse drug reactions and burgeoned genetically diverse resistant strains create a big barrier in the treatment, thereby demanding novel proof-of-concept ligands and breakthrough medicines. Hence, as a follow-up of the previous proteomics study against 53 H. pylori strains, KdsB was identified as a vital conserved-target enzyme. Herein, the rational therapeutic-design strategies exploiting for such a hidden cryptic inhibitor were utilized in lead-optimization campaigns through shape screening, the powerful scaffold-hopping, rigid-receptor, quantum-polarized ligand and induced-fit docking techniques coupled with estimating molecular-mechanics energies (ΔGbind) through generalized-Born and surface-area-continuum solvation. Variable-dielectric-Surface-Generalized Born, a novel energy model and physics-based corrections for bond-interactions and ADME/Tox predictions led to yield improved eight therapeutic chemical entities with positive synthesizability scores (0–1). Long-range molecular dynamics (300 ns) simulations revealed stability of leads. Significant computational findings with better competitive binding-strengths than experimental ligands could pave the best choice for selecting better leads as it warrants and filter false-positives based on the consensus of scaffolds interactions and suggesting that designed novel class of KdsB-antagonist molecules may dysfunction the target and stimulate new insights for developing effectual medical interventions.

A myriad of drug-resistant strains of Helicobacter pylori and adverse drug-reactions create a big-barrier in the treatment, thereby demanding novel proof-of-concept inhibitors and breakthrough medicines. Hence, an affinity-centric protocol was devised to implement scaffold-design for 3-dehydroquinate dehydratase-II (AroQ) as a follow-up of our study against beaucoup strains. Herein, the study focuses on preferred the attractive-target methodically due to its salient features include conserving, essential and specific for H. pylori, not present in humans and gut-flora. Structural refinement, energy minimization and optimization of the developed best-model were employed with confirming active site residues around substrate. Published AroQ-inhibitors and substrate were utilized to probe an in-house library of molecules. The prepared dataset was allowed to lead-optimization campaign includes rigid-receptor docking through high-throughput virtual, standard-precision, extra-precision screening filters, quantum-polarized-ligand (quantum mechanical and molecular mechanical (QM/MM)) and induced-fit docking experiments. Convergence threshold (0.05) and Truncated Newton Conjugate Gradient (TNCG) were set in ConfGen's algorithm to produce high-quality bioactive conformations by thoroughly narrowing the conformational space accessible to the leads. ADME/Tox predictions and long-range molecular dynamics simulations were executed after post-docking evaluations. The approach provided seven ranked compounds with better scoring functions, bioactive-conformers and pharmacokinetics profiles than published ligands and substrate. Simulations revealed more consistency of lead1–AroQ complex throughout chemical time than controls in the formulated physiological milieu. The study outcomes showing the good competitive binding propensity for active-tunnel over the substrate and previous ligands, thereby these leads could be ideal for proposing as selective cutting-edge inhibitors to target AroQ specific for H. pylori strains.

Gram-negative bacteria show more drug-resistant than Gram-positive bacteria due to unique structural attribute and cause significant morbidity and mortality across the globe. Such characteristic structure is an organelle lipopolysaccharide (LPS) on the outer membrane (OM) of cell wall essential for growth and survival of bacteria. LPS is a major cell wall component formed by dedicated transenvelope multiprotein complexes that shield the underlying peptidoglycan layer and play a key role in host–pathogen interactions with the innate immune system. Moreover, which constitutes the surface-exposed molecules with lipid portion in the outer leaflet of the OM that able to show antibiotic resistance and also responsible for the variety of biological effects associated with bacterial sepsis. LPS synthesis and structure are a conserved subject in infections during bacterial adaptive changes. Such changes ensue immune evasion, prolonged inflammation and augmented antibiotic resistance by working as molecular decoys which titrate the antimicrobials away from its intracellular antibiotic target. Herein, this review summarises the key features of LPS structure, function and biosynthesis. Moreover, it highlights the broad-spectrum conserved targets in the Raetz pathway without an alternative way for LPS biosynthesis vital for the development of novel therapeutic interventions against Gram-negative pathogens.

Matrix metalloproteinases (MMPs) are secretary or membrane type proteolytic enzymes that act on extracellular matrix protein components such as collagens, gelatins, elastins, laminins, fibronectins, and integrins. MMPs are synthesized as zymogens and are activated to functional forms on autoproteolysis or by other proteases. Naturally, the activity of MMPs was regulated by specific tissue inhibitors of metalloproteinases and transcriptionally regulated by miRNAs. MMPs have an important role in tissue remodeling by regulating cell death, morphogenesis, and wound healing activity. Overexpression of MMPs leads to various pathologies predominantly cancer, cardiovascular, and neurological diseases. Impact of MMPs on breast cancer progressions such as proliferation, angiogenesis, invasion, and metastasis are focused in this review.

c-Jun-NH2 terminal kinases (JNKs) come under a class of serine/threonine protein kinases and are encoded by three genes, namely JNK1, JNK2 and JNK3. Human JNK1 is a cytosolic kinase belonging to mitogen-activated protein kinase (MAPK) family, which plays a major role in intracrinal signal transduction cascade mechanism. Overexpressed human JNK1, a key kinase interacts with other kinases involved in the etiology of many cancers, such as skin cancer, liver cancer, breast cancer, brain tumors, leukemia, multiple myeloma and lymphoma. Thus, to unveil a novel human JNK1 antagonist, receptor-based pharmacophore modeling was performed with the available eighteen cocrystal structures of JNK1 in the protein data bank. Eighteen e-pharmacophores were generated from the 18 cocrystal structures. Four common e-pharmacophores were developed from the 18 e-pharmacophores, which were used as three-dimensional (3D) query for shape-based similarity screening against more than one million small molecules to generate a JNK1 ligand library. Rigid receptor docking (RRD) performed using GLIDE v6.3 for the 1683 compounds from in-house library and 18 cocrystal ligands with human JNK1 from lower stringency to higher stringency revealed 17 leads. Further to derive the best leads, dock complexes obtained from RRD were studied further with quantum-polarized ligand docking (QPLD), induced fit docking (IFD) and molecular mechanics/generalized Born surface area (MM-GBSA). Four leads have showed lesser binding free energy and better binding affinity towards JNK1 compared to 18 cocrystal ligands. Additionally, JNK1-lead1 complex interaction stability was reasserted using 50 ns MD simulations run and also compared with the best resolute cocrystal structure using Desmond v3.8. Thus, the results obtained from RRD, QPLD, IFD and MD simulations indicated that lead1 might be used as a potent antagonist toward human JNK1 in cancer therapeutics.