Computational Bio prospecting of Phyto - constituents as potential inhibitors for Peptide deformylase from Streptococcus oralis: an opportunistic pathogen.

Streptococcus oralis an opportunistic bacterium has been reported to be involved in various blood borne infections like subacute bacterial endocarditis, septicaemia, bacterial meningitis and in some cases dental caries too. Among various targets the peptide deformylase, of S.oralis appears to be most potent druggable target as it is involved in protein synthesis is opted for the current study. Due to unavailability of PDB structure of peptide deformylase from S. oralis the study initiates with homology modelling of the protein and 6OW2 of S pneumoniae is considered as the template. Thereafter, Molecular docking, Molecular dynamic simulation, ADME analysis, and MMPBSA analysis was carried out to explore the inhibitory potential of phyto-constituents as potential inhibitors for Peptide deformylase from S.oralis. Actinonin was considered as reference drug. Among 2370 phyto compounds the best observations were recorded for A1-Barrigenol (IMPHY010984) with binding affinity of -8.5kcal/mol. Calculated RMSD, RMSF, Binding Free Energy for IMPHY010984 averaged at about 0.10±0.03nm, 0.08±0.05nm, 131±21kJ/mol respectively whereas the RMSD, RMSF, Binding Free Energy recorded for reference drug averaged at about 0.19±0.04nm, 0.11±0.08nm, -94±18kJ/mol respectively. Based on in silico observations IMPHY010984 is proved out as superior candidate over reference drug. The study reflects the potential of IMPHY010984 as prophylactic therapeutics for S.oralis.

A computational investigation of potential plant-based bioactive compounds against drug-resistant Staphylococcus aureus of multiple target proteins.

Drug-resistant Staphylococcus aureus (DRSA) poses a significant global health threat, like bacteremia, endocarditis, skin, soft tissue, bone, and joint infections. Nowadays, the resistance against conventional drugs has been a prompt and focused medical concern. The present study aimed to explore the inhibitory potential of plant-based bioactive compounds (PBBCs) against effective target proteins using a computational approach. We retrieved and verified 22 target proteins associated with DRSA and conducted a screening process that involved testing 87 PBBCs. Molecular docking was performed between screened PBBCs and reference drugs with selected target proteins via AutoDock. Subsequently, we filtered the target proteins and top PBBCs based on their binding affinity scores. Furthermore, molecular dynamic simulation was carried out through GROMACS for a duration of 100 ns, and the binding free energy was calculated using the gmx_MMPBSA. The result showed consistent hydrogen bonding interactions among the amino acid residues Ser 149, Arg 151, Thr 165, Thr 216, Glu 239, Ser 240, Ile 14, as well as Asn 18, Gln 19, Lys 45, Thr 46, Tyr 109, with their respective target proteins of the penicillin-binding protein and dihydrofolate reductase complex. Additionally, we assessed the pharmacokinetic properties of screened PBBCs via SwissADME and AdmetSAR. The findings suggest that ß-amyrin, oleanolic acid, kaempferol, quercetin, and friedelin have the potential to inhibit the selected target proteins. In future research, both in vitro and in vivo, experiments will be needed to establish these PBBCs as potent antimicrobial drugs for DRSA.Communicated by Ramaswamy H. Sarma.

Microstructure, Mechanical, In Vitro Biodegradation, and Antimicrobial Behavior of a Mg-Zn-Ca-Sr/ZrO2 Composite Prepared Using Powder Metallurgy.

Biodegradable materials, especially Mg alloys, have an exceptional advantage over nonbiodegradable materials in orthopedic applications, such as avoiding second surgery for removal/replacement, stress shielding, but not enough mechanical strength, and so forth. By further improving the Mg alloy to get all the remaining required properties, it can be used for better biodegradable implants, which depend adequately on material optimization, processing, and so forth. A Mg-Zn-Ca-Sr/ZrO2 composite has been prepared using powder metallurgy by adding 0, 1, 2, and 3 wt % of ZrO2, which also contains Zn, Ca, and Sr as nutrient elements. Microstructure characterization, as well as mechanical and in vitro biodegradation, have been investigated by hardness, compression, and immersion tests. The highest compressive strength, contraction, and hardness of about 185.6 MPa, 9.5%, and 65.2 HRB are observed in the 2% ZrO2-containing composite, respectively, whereas a minimum biodegradation rate of 2.76 mm/year is observed on the same. The antibiotic sensitivity observations against Staphylococcus aureus suggest that the alloy C3 has superior biological activity against the pathogen which ranks this alloy on top in merit. Overall, Mg-Zn-Ca-Sr/ZrO2 exhibits impressive potential for use as a biodegradable and antibiotic material for orthopedic applications.

A Parametric Targetability Evaluation Approach for Vitiligo Proteome Extracted through Integration of Gene Ontologies and Protein Interaction Topologies.

Vitiligo is a well-known skin disorder with complex etiology. Vitiligo pathogenesis is multifaceted with many ramifications. A computational systemic path was designed to first propose candidate disease proteins by merging properties from protein interaction networks and gene ontology terms. All in all, 109 proteins were identified and suggested to be involved in the onset of disease or its progression. Later, a composite approach was employed to prioritize vitiligo disease proteins by comparing and benchmarking the properties against standard target identification criteria. This includes sequence-based, structural, functional, essentiality, protein-protein interaction, vulnerability, secretability, assayability, and druggability information. The existing information was seamlessly integrated into efficient pipelines to propose a novel protocol for assessment of targetability of disease proteins. Using the online data resources and the scripting, an illustrative list of 68 potential drug targets was generated for vitiligo. While this list is broadly consistent with the research community's current interest in certain specific proteins, and suggests novel target candidates that may merit further study, it can still be modified to correspond to a user-specific environment, either by adjusting the weights for chosen criteria (i.e., a quantitative approach) or by changing the considered criteria (i.e., a qualitative approach).

Construction of a Comprehensive Protein-Protein Interaction Map for Vitiligo Disease to Identify Key Regulatory Elements: A Systemic Approach.

Vitiligo is an idiopathic disorder characterized by depigmented patches on the skin due to progressive loss of melanocytes. Several genetic, immunological, and pathophysiological investigations have established vitiligo as a polygenetic disorder with multifactorial etiology. However, no definite model explaining the interplay between these causative factors has been established hitherto. Therefore, we studied the disorder at the system level to identify the key proteins involved by exploring their molecular connectivity in terms of topological parameters. The existing research data helped us in collating 215 proteins involved in vitiligo onset or progression. Interaction study of these proteins leads to a comprehensive vitiligo map with 4845 protein nodes linked with 107,416 edges. Based on centrality measures, a backbone network with 500 nodes has been derived. This has presented a clear overview of the proteins and processes involved and the crosstalk between them. Clustering backbone proteins revealed densely connected regions inferring major molecular interaction modules essential for vitiligo. Finally, a list of top order proteins that play a key role in the disease pathomechanism has been formulated. This includes SUMO2, ESR1, COPS5, MYC, SMAD3, and Cullin proteins. While this list is in fair agreement with the available literature, it also introduces new candidate proteins that can be further explored. A subnetwork of 64 vitiligo core proteins was built by analyzing the backbone and seed protein networks. Our finding suggests that the topology, along with functional clustering, provides a deep insight into the behavior of proteins. This in turn aids in the illustration of disease condition and discovery of significant proteins involved in vitiligo.

Computational model for pathway reconstruction to unravel the evolutionary significance of melanin synthesis.

Melanogenesis is a complex multistep process of high molecular weight melanins production by hydroxylation and polymerization of polyphenols. Melanins have a wide range of applications other than being a sun - protection pigment. Melanogenesis pathway exists from prokaryotes to eukaryotes. It has evolved over years owing to the fact that the melanin pigment has different roles in diverse taxa of organisms. Melanin plays a pivotal role in the existence of certain bacteria and fungi whereas in higher organisms it is a measure of protection against the harmful radiation. We have done a detailed study on various pathways known for melanin synthesis across species. It was divulged that melanin production is not restricted to tyrosine but there are other secondary metabolites that synthesize melanin in lower organisms. Furthermore the phylogenetic study of these paths was done to understand their molecular and cellular development. It has revealed that the melanin synthesis paths have co-evolved in several groups of organisms. In this study, we also introduce a method for the comparative analysis of a metabolic pathway to study its evolution based on similarity between enzymatic reactions.

Genomes to hits in silico - a country path today, a highway tomorrow: a case study of chikungunya.

These are exciting times for bioinformaticians, computational biologists and drug designers with the genome and proteome sequences and related structural databases growing at an accelerated pace. The post-genomic era has triggered high expectations for a rapid and successful treatment of diseases. However, in this biological information rich and functional knowledge poor scenario, the challenges are indeed grand, no less than the assembly of the genome of the whole organism. These include functional annotation of genes, identification of druggable targets, prediction of three-dimensional structures of protein targets from their amino acid sequences, arriving at lead compounds for these targets followed by a transition from bench to bedside. We propose here a "Genome to Hits In Silico" strategy (called Dhanvantari) and illustrate it on Chikungunya virus (CHIKV). "Genome to hits" is a novel pathway incorporating a series of steps such as gene prediction, protein tertiary structure determination, active site identification, hit molecule generation, docking and scoring of hits to arrive at lead compounds. The current state of the art for each of the steps in the pathway is high-lighted and the feasibility of creating an automated genome to hits assembly line is discussed.