Iftikhar Aslam Tayubi

Influence of V54M mutation in giant muscle protein titin: a computational screening and molecular dynamics approach

Recent genetic studies have revealed the impact of mutations in associated genes for cardiac sarcomere components leading to dilated cardiomyopathy (DCM). The cardiac sarcomere is composed of thick and thin filaments and a giant muscle protein known as titin or connectin. Titin interacts with T-cap/telethonin in the Z-line region and plays a vital role in regulating sarcomere assembly. Initially, we screened all the variants associated with giant protein titin and analyzed their impact with the aid of pathogenicity and stability prediction methods. V54M mutation found in the hydrophobic core region of the protein associated with abnormal clinical phenotype leads to DCM was selected for further analysis. To address this issue, we mapped the deleterious mutant V54M, modeled the mutant protein complex, and deciphered the impact of mutation on binding with its partner telethonin in the titin crystal structure of PDB ID: 1YA5 with the aid of docking analysis. Furthermore, two run molecular dynamics simulation was initiated to understand the mechanistic action of V54M mutation in altering the protein structure, dynamics, and stability. According to the results obtained from the repeated 50 ns trajectory files, the overall effect of V54M mutation was destabilizing and transition of bend to coil in the secondary structure was observed. Furthermore, MMPBSA elucidated that V54M found in the Z-line region of titin decreases the binding affinity of titin to Z-line proteins T-cap/telethonin thereby hindering the protein–protein interaction.

A Molecular Docking and Dynamics Approach to Screen Potent Inhibitors Against Fosfomycin Resistant Enzyme in Clinical Klebsiella pneumoniae : IDENTIFICATION OF POTENT INHIBITORS AGAINST FosA VARIANT-7

Klebsiella pneumoniae, BA6753 was cultured from a patient in the Clinical Microbiology Laboratory of Christian Medical College. K. pneumoniae, BA6753 has a multidrug resistance plasmid encoding novel FosA variant‐7, fosfomycin resistance enzyme. Minimal side effects and a wide range of bactericidal activity of fosfomycin have resulted in its expanded clinical use that prompts the rise of fosfomycin‐resistant strains. At present, there are no effective inhibitors available to conflict the FosA‐medicated fosfomycin resistance. To develop effective FosA inhibitors, it is crucial to understand the structural and dynamic properties of resistance enzymes. Hence, the present study focuses on the identification of potent inhibitors that can effectively bind to the fosfomycin resistance enzyme, thus predispose the target to inactivate by the second antibiotic. Initially, a series of active compounds were screened against the resistant enzyme, and the binding affinities were confirmed using docking simulation analysis. For efficient activity, the binding affinity of the resistance enzyme ought to be high with the inhibitor than the fosfomycin drug. Consequently, the enzyme‐ligand complex which showed higher binding affinity than the fosfomycin was employed for subsequent analysis. The stability of the top scoring enzyme‐ligand complex was further validated using molecular dynamics simulation studies. On the whole, we presume that the compound 19583672 demonstrates a higher binding affinity for the resistance enzyme comparing to other compounds and fosfomycin. We believe that further enhancement of the lead compound can serve as a potential inhibitor against resistance enzyme in drug discovery process. J. Cell. Biochem. 118: 4088–4094, 2017.

Computational insights into the molecular interactions of environmental xenoestrogens 4-tert-octylphenol, 4-nonylphenol, bisphenol A (BPA), and BPA metabolite, 4-methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene (MBP) with human sex hormone-binding globulin

Environmental contamination has been one of the major drawbacks of the industrial revolution. Several man-made chemicals are constantly released into the environment during the manufacturing process and by leaching from the industrial products. As a result, human and animal populations are exposed to these synthetic chemicals on a regular basis. Many of these chemicals have adverse effects on the physiological functions, particularly on the hormone systems in human and animals and are called endocrine disrupting chemicals (EDCs). Bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) are three high volume production EDCs that are widely used for industrial purposes and are present ubiquitously in the environment. Bisphenol A is metabolized in the human body to a more potent compound (MBP: 4-Methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene). Epidemiological and experimental studies have shown the three EDCs to be associated with adverse effects on reproductive system in human and animals. Sex hormone-binding globulin (SHBG) is a circulatory protein that binds sex steroids and is a potential target for endocrine disruptors in the human body. The current study was done in order to understand the binding mechanism of OP, BPA, NP, and MBP with human SHBG using in silico approaches. All four compounds showed high binding affinity with SHBG, however, the binding affinity values were higher (more negative) for MBP and NP than for OP and BPA. The four ligands interacted with 19-23 residues of SHBG and a consistent overlapping of the interacting residues for the four ligands with the residues for the natural ligand, dihydrotestosterone (DHT; 82-91% commonality) was shown. The overlapping SHBG interacting residues among DHT and the four endocrine disruptors suggested that these compounds have potential for interference and disruption in the steroid binding function.

Prospects and progress in the production of valuable carotenoids: Insights from metabolic engineering, synthetic biology, and computational approaches

Carotenoids are isoprenoid pigments synthesized exclusively by plants and microorganisms and play critical roles in light harvesting, photoprotection, attracting pollinators and phytohormone production. In recent years, carotenoids have been used for their health benefits due to their high antioxidant activity and are extensively utilized in food, pharmaceutical, and nutraceutical industries. Regulation of carotenoid biosynthesis occurs throughout the life cycle of plants, with vibrant changes in composition based on developmental needs and responses to external environmental stimuli. With advancements in metabolic engineering techniques, there has been tremendous progress in the production of industrially valuable secondary metabolites such as carotenoids. Application of metabolic engineering and synthetic biology has become essential for the successful and improved production of carotenoids. Synthetic biology is an emerging discipline; metabolic engineering approaches may provide insights into novel ideas for biosynthetic pathways. In this review, we discuss the current knowledge on carotenoid biosynthetic pathways and genetic engineering of carotenoids to improve their nutritional value. In addition, we investigated synthetic biological approaches for the production of carotenoids. Theoretical biology approaches that may aid in understanding the biological sciences are discussed in this review. A combination of theoretical knowledge and experimental strategies may improve the production of industrially relevant secondary metabolites.

Influence of PCOS in Obese vs. Non-Obese women from Mesenchymal Progenitors Stem Cells and Other Endometrial Cells: An in silico biomarker discovery

Polycystic ovary syndrome (PCOS) is endocrine system disease which affect women ages 18 to 44 where the women’s hormones are imbalance. Recently it has been reported to occur in early age. Alteration of normal gene expression in PCOS has shown negative effects on long-term health issues. PCOS has been the responsible factor for the infertility in women of reproductive age group. Early diagnosis and treatment can improve the women’s health suffering from PCOS. Earlier Studies shows correlation of PCOS upon insulin resistance with significant outcome, Current study shows the linkage between PCOS with obesity and non-obese patients. Gene expression datasets has been downloaded from GEO (control and PCOS affected patients). Normalization of the datasets were performed using R based on RMA and differentially expressed gene (DEG) were selected on the basis of p-value 0.05 followed by functional annotation of selected gene using Enrich R and DAVID. The DEGs were significantly related to PCOS with obesity and other risk factors involved in disease. The Gene Enrichment Analysis suggests alteration of genes and associated pathway in case of obesity. Current study provides a productive groundwork for specific biomarkers identification for the accurate diagnosis and efficient target for the treatment of PCOS.

Computationally designed novel drug for the regulation of protein expression levels of BCL-2 family

One of the key regulatory proteins in apoptosis, B-Cell Lymphoma 2 and its family exhibit irregular levels in autistic cerebellum. The objective of this research study is to formulate a drug which aids in regulation of the protein expression levels of B-cell CLL/lymphoma 2 (BCL-2) family. A novel drug was designed with Navitoclax and BAX Channel inhibitor as primary components. The novel drug displayed satisfactory binding properties with the regulatory proteins. The novel drug displayed non-carcinogenic and nonmutagenic properties when tested with TOPKAT pipeline. Computational analysis suggested some symptoms of mild irritancy and predicted drug as not readily aerobic biodegradable. The entire set of calculated absorption, distribution, metabolism, excretion and toxicity (ADMET) and the pharmacological properties of the drug suggest it can be tested for experimental studies as a candidate drug.

Protein Misfolding and Amyloid Formation in Alzheimer’s Disease

The information necessary for proteins to correctly fold into biologically active three dimensional (3D) structures is present in the amino acid sequence. The ways by which proteins fold still remain one of the unexplained mysteries in the field of protein biochemistry. Investigating the impact and consequences of protein misfolding can help decipher the molecular causes behind the complex amyloid diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. Various participating molecular entities like amyloid beta (Aβ), tau protein, and non-beta sheets are facilitating the pathogenesis of Alzheimer’s disease. Understanding their structure as well as their mechanism of action is useful to decode the therapeutic treatment for these complex diseases.

Identification of hub genes and their SNP analysis in West Nile virus infection for designing therapeutic methodologies using RNA-Seq data

The West Nile virus (WNV) infections are generally asymptomatic and are considered as immediate concerns of biodefense due to the lack of any therapeutic remedies. In this work, we created an interaction network of 1159 differentially expressed genes to detect potential hub genes from WNV infected primary human macrophages. We go on to explore the genetic variations that can alter the expression and function of identified hub genes (HCLS1, SLC15A3, HCK, and LY96) using the PROVEAN Protein Batch tool and PolyPhen-2. Community analysis of the network revealed that these clusters were enriched in GO terms such as inflammatory response and regulation of proliferation. Analysis of hub genes can aid in determining their degree of conservation and may help us in understanding their functional roles in biological systems. The nsSNPs proposed in this work may be further targeted through experimental methods for improving treatment towards the infection of WNV.

In silico analysis of detrimental mutation in EPHB2 gene causing Alzheimer’s disease

Background EPHB2 (Ephrin Receptor B2) are instrumental in signaling pathways like MAPK mediating tumour suppression, progenitor cell proliferation etc. [1,2]. Previous research has investigated the possibility that disrupted EphB2NMDA R binding is relevant to the development of Alzheimer’s disease (AD), a condition that is characterized by severe synaptic impairment. Hence it can be inferred the role of EPHB2 and associated single nucleotide polymorphism is essential in studying the signaling pathways as well as neurodevelopmental processes associated with it. Studying the impact of the protein and the associated non-synonymous SNPS can also decode the role of genetic variations with respect to the role of the protein in the signaling pathway as well as susceptibility towards the disease. Materials and methods The protein sequence data for EPHB2 [Accession ID: P29323.5] was collected from NCBI protein sequence database. SNP information for the computational analysis was obtained from NCBI dbSNP and Ensemble Gene Browser. Structure of EPHB2 protein was obtained from RCSB Protein Data Bank. (PDB ID:2QBX). A point mutation in native EPHB2 protein at position 80, Arginine (R) to Histidine (H) was introduced using SPDB Viewer package (Figure 1). We used SIFT, Polyphen, PhD-SNP and MutPred tools in order to examine the lethal nsSNPs occurring in the EPHB2 coding region. We filtered the most pathological mutation by combining the scores of then above servers. We implemented SNP Effect 4.0 to examine the possible phenotypic consequences at molecular, cellular, and individual level. Volume of the recep-