Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

Department of Biotechnology

Staphylokinase (SAK), the thrombolytic protein holds a significant position in treating cardiovascular diseases. However, the rapid clearance of this protein from blood circulation reduces its effective usage and as a strategy to increase the half-life of SAK, initial work focussed on lipid modification of SAK (LMSAK) in E. coli GJ1158. Effective purification of the modified protein achieved using the two step method of hydrophobic interaction chromatography in succession with size exclusion chromatography, indicated a better yield. The thrombolytic activity of purified LMSAK analysed in heated plasma agar plate assay confirmed an enhanced activity. In vivo pharmacokinetic studies carried out for determining the half-life of LMSAK in blood circulation of mice presented that it has a half-life of 43.3 ± 3.4 min which is much higher than 21.6 ± 2.1 min that of the unmodified version of SAK. The studies confirmed the role of lipid modification as a crucial factor in confirming in vivo stability of LMSAK and proves to be beneficial in therapeutic usage. © 2020 International Alliance for Biological Standardization

World University root node

School of Bio Sciences and Technology

Vellore Campus

Biologicals

Purification and in vivo stability and half-life of recombinant lipid modified staphylokinase

Over the years, phytochemical compounds have shown compelling evidences in exhibiting powerful antitumor properties. Moreover, due to the lack of safety and high cost of cancer therapies, opportunities are being sought out in these compounds as an alternative treatment modality. Therefore, in the present study, 1,574 compounds from NPACT library were examined to excavate potent and nontoxic anaplastic lymphoma kinase (ALK) inhibitors. Notably, two pharmacophore hypotheses (AAAHP and DDRRR) were generated using ligand-based and energy-based techniques, respectively, to eliminate false-positive prediction in database screening. Furthermore, molecular docking and Prime MM/GBSA analysis were performed on the screened compounds to examine inhibitory activity against ALK. The analysis revealed that the two hits, namely, NPACT00018 and NPACT01077, exhibited better docking scores, binding energies, and also ensured excellent drug-likeness properties than the reference compound, crizotinib. Finally, the results were subjected to molecular dynamics studies to gain insight into the stability of these compounds in the binding pocket of ALK protein. Indeed, the useful predictions generated by the present computational models are of immense importance and could further speed up the anticancer drug development in the near future. © 2020 International Union of Biochemistry and Molecular Biology, Inc.

Biotechnology and Applied Biochemistry

Discovery of anaplastic lymphoma kinase inhibitors from natural product library: A holistic in silico approach

Background: The Human Genome Project has unleashed the power of genomics in clinical practice as a choice of individualized therapy, particularly in cancer treatment. Pharmacogenomics is an interdisciplinary field of genomics that deals with drug response, based on individual genetic makeup. Objective: The main genetic events associated with carcinogenesis activate oncogenes or inactivate tumor-suppressor genes. Therefore, drugs should be specific to inactivate or regulate these mutant genes and their protein products for effective cancer treatment. In this review, we summarize how polymedication decisions in cancer treatments based on the evaluation of cytochrome P450 (CYP450) polymorphisms are applied for pharmaco-genetic assessment of anticancer therapy outcomes. Results: However, multiple genetic events linked, inactivating a single mutant gene prod-uct, may be insufficient to inhibit tumor progress. Thus, genomics and pharmacogenetics directly influence a patient’s response and aid in guiding clinicians to select the safest and most effective combination of medications for a cancer patient from the initial prescrip-tion. Conclusion: This review outlines the roles of oncogenes, the importance of cytochrome P450 (CYP450) in cancer susceptibility, and its impact on drug metabolism, proposing combined approaches to achieve precision therapy. © 2020 Bentham Science Publishers.

Current Pharmacogenomics and Personalized Medicine

Oncogenomics and CYP450 implications in personalized cancer therapy

PTEN is a tumour suppressor gene known for regulating apoptosis, cell growth, and many other pathways. It is one of the most frequently mutated genes comprising the phosphatase domain (PD) and C terminal domain (C2). Direct therapeutic methods are not applicable for targeting PTEN because once gets mutated, it needs restoration. For mutant detection and restoration using PTEN mRNA there is a need to explore various mutations taking place in PTEN, identify their particular domains, and study their interactions within the cellular system. Here, we have tried to highlight a few such regions in the mutated PTEN of breast cancer patients. In this study, we have selected the top-most-occurring PTEN mutation in breast cancer and compared them to determine the specific properties of each mutation and its effect on functionality. Molecular dynamic simulation for 50 ns was performed on five structures to compare the structural behaviour of mutated PTEN in the system. Our finding suggests that frameshift mutations are more damaging and affect the c2 domain. Frameshift mutant fs_ACTT is the highest occurring as well as the most damaging mutation in all the compared structures. Docking study shows that substitution mutations D92H and R130Q causes loss of binding ability towards PIP2 in normal PTEN, interfering the dephosphorylation process. Overall, the C2 domain is more frequently mutated, and the amino acid residues in the C2 domain show more fluctuations compared to the other regions. Our study can provide the basis for selecting frequently mutated C2 domain as a potential therapeutic marker. Communicated by Ramaswamy H. Sarma. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Journal of Biomolecular Structure and Dynamics

Molecular dynamic study on PTEN frameshift mutations in breast cancer provide c2 domain as a potential biomarker

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and is characterized by degeneration and axon loss from the upper motor neuron, that descends from the lower motor neuron in the brain. Over the period, assorted outcomes from medical findings, molecular pathogenesis, and structural and biophysical studies have abetted in providing thoughtful insights underlying the importance of disease-causing genes in ALS. Consequently, numerous mechanisms were proposed for the pathogenesis of ALS, considering protein mutations, aggregation, and misfolding. Besides, the answers to the majority of ALS cases that happen to be sporadic still remain obscure. The application in discovering susceptibility factors in ALS contemplating the genetic factors is to be further dissevered in the future years with innovation in research studies. Hence, this review targets in revisiting the breakthroughs on the disease-causing genes related with ALS. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Journal of Molecular Neuroscience

A Systematic and Comprehensive Review on Disease-Causing Genes in Amyotrophic Lateral Sclerosis

Antimicrobial peptides (AMPs) like tritrpticins, exhibit non-specific membrane lysis of gram-negative bacteria and can replace antibiotics, combating multi-drug resistance observed in UTI patients. Tritrpticins designated–NT, T1, T2, T3, T5, T7 and T8, were computationally investigated by interaction with Escherichia coli membrane model, mammalian cell toxicity and structural stability to identify a potential drug scaffold for UTI. Initially T3 was eliminated due to low interaction with Escherichia coli membrane model, based on its computed solvation energy. Further, negative support vector machine (SVM) scores revealed non-toxicity of T1, T2, T5, T7 and T8. Finally, at 310 K and varying pH 4.5–9.0, T5 exhibited highest structural stability based on its highest consistency of hydrogen bonds (H-bonds), root mean square deviation (RMSD) and secondary structure profiles along with its lowest conformational free energy. Overall, T5 could be considered a promising peptide drug scaffold to combat UTI. ABBREVIATIONSAMP antimicrobial peptidePBEQ Poisson Boltzmann equationH-bonds hydrogen bondsMIC minimum inhibitory concentrationLD50 lethal dose, 50%RMSD root mean square deviationSVM support vector machineUTI urinary tract infection Communicated by Ramaswamy H. Sarma. © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Identification of therapeutic peptide scaffold from tritrpticin family for urinary tract infections using in silico techniques

Whole exome sequencing is an adept method to reveal novel and disease-related SNPs and INDELs as it screen the actionable areas of the genome. We evaluated the exome sequenced datasets of patients with Parkinson's disease (PD) in South African ethnic origin. The primary focus of this study was to discover the SNPs and INDELs patterns responsible for PD. The variant discovery was performed with genome analysis tool kit best practices variant detection pipelines. The SNPs were linked to the genes and categorized based on the filter-based annotation from ANNOVAR. We identified a total of 7955 SNPs and 9952 INDELs in all seven datasets together. A total of 130 missense nsSNPs were prioritized based on its damaging effect predicted from SIFT and Polyphen2 annotation. We noticed a novel nsSNP rs111655870 in gene LRRK2 that shows the mutation of a Leucine to Phenylalanine at position 208 which can alter the protein function. The study also filtered seven nsSNPs in genes NAGA, SULT4A1, MYH8, FLNA, TPM3, ATP13A1, CLN8 that have potentially deleterious effects predicted by various computational tools. This analysis suggested that the above filtered nsSNPs and INDELs have a functional impact and provide the footing for genetic studies related to PD. Further screening of these variations provides deeper insight for molecular mechanism of disease progression. © 2020

Genomics

Next generation sequencing exome data analysis aids in the discovery of SNP and INDEL patterns in Parkinson's disease

The missense mutation in the mismatch repair gene MSH2 underlies in several hereditary cancers. In this study, we have detailed the disruptive mutation of G322D that overtly pathogenic and clinically relevant to the triple negative breast cancer (TNBC) on the basis of structural aspect to untangle the unknown factors. We systematically evaluated the conformational changes that undergo upon mutation from the annotation of intra-residual contacts, secondary structural arrangements and fold recognition through molecular dynamics simulation. At first, we interpreted the total of 88 intra-molecular interaction which is required minimally to maintain the native structural architecture. Adequately, the molecular dynamics approach is well contributed toward structural modification that takes places in C-terminal linking 290–294(L20), 339–347(L23-T16- α9-T17) and 373–395(α12-T19-20-L26-T21-L27-T22) in contrast to native 290–294(β8), 339–347(T20-α9-T21-α10), 373–395(α12-T19-20-L26-T21-L27-T22) provides a straightforward evidence that is underpinning destabilization and protein misfolding. Eventually, we have highlighted the structural debilitation of G322D in the core region of 303–309 L23-T18-α6 - L21- α8, and 326–330 α7-T19-L25 -α9 notably the connecting elements of secondary structural propensity (loop-helix) in folding pack were completely abrupted which helps to keep native form. Essentially, the information gained in our study on residual interaction and conformational transitions in the structure of mutant MSH2 provides valuable insights to understand the clues of functional behavior and also pave the way to frame suitable and improved therapeutical targets. Communicated by Ramaswamy H. Sarma. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Structural debilitation of mutation G322D associated with MSH2 and their role in triple negative breast cancer

Background: The increasing cases of non-small cell lung cancer pose a relentless threat to human health. Therefore, using fragment-based drug discovery as the modus operandi, the present study aimed to design small molecule inhibitors for Anaplastic Lymphoma Kinase (ALK) positive Non-Small Cell Lung Cancer (NSCLC) and for its secondary mutation (F1174L). Materials and methods: A total of 12 ALK inhibitors (both FDA and clinical) reported in the literature was utilised in the present study to design the novel and potent ALK inhibitors. Fragment script and BREED of Schrödinger suite was used to generate novel structural combinations. GLIDE algorithm was employed to identify the fragments with high binding affinity to the native and mutant forms of ALK. Screened out fragments were subjected to ADMET analysis. Additionally, the impact of F1174L mutation in the stability of ALK protein was assessed using SDM and I-Mutant tools. RING algorithm was employed to compare the pattern of intramolecular interaction between the native and F1174L ALK protein. Results: A novel hybrid molecule LF16 was identified with better binding, superior CNS activity, higher drug score and low toxicity. Annihilation of intramolecular interactions with Ile 1179, Ile 1170 and Phe1098 were found to be the cause of the destabilizing effect of the mutant protein. Of note, these residues were found to play important roles in the formation of F-core as well as in stabilizing αC-helix, which is important for maintaining the inactive form of ALK. Moreover, Conclusion: We believe that these results could foster the designing and development of novel ALK inhibitors towards the management of crizotinib resistance in the near future. © 2020, Association of Pharmaceutical Teachers of India. All rights reserved.

VIT Unitversity

Fulltext

Indian Journal of Pharmaceutical Education and Research

Design of ALK Inhibitors for Non-Small Cell Lung Cancer – A Fragment Based Approach

Background and aims: Ovarian cancer (OC) is the seventh most commonly detected cancer among women. This study aimed to map the hub and core genes and potential pathways that might be involved in the molecular pathogenesis of OC. Methods: In the present work, we analyzed a microarray dataset (GSE126519) from the Gene Expression Omnibus (GEO) database and used the GEO2R tool to screen OC cells and ovarian SINE-resistant cancer cells for differentially expressed genes (DEGs). For the functional annotation of the DEGs, we conducted Gene Ontology (GO) and pathway enrichment analyses (KEGG) using the DAVID v6.8 online server and GenoGo Metacore™, Cortellis Solution software. Protein–protein interaction (PPI) networks were constructed using the STRING database, and Cytoscape software was used for visualization. The survival analysis was performed using the online platform GEPIA2 to determine the prognostic value of the expression of hub genes in cell lines from OC patients. Results: We identified a total of 809 upregulated and 700 downregulated DEGs. GO analysis revealed that the genes with statistically significant differences in expression were mainly associated with biological processes involved in the cell cycle, the mitotic cell cycle, mitotic nuclear division, organ morphogenesis, cell development, and cell morphogenesis. By using the Analyze Networks (AN) algorithm in GeneGo, we identified the most relevant biological networks involving DEGs that were mainly enriched in the cell cycle (in metaphase checkpoints) and revealed the role of APC in cell cycle regulation pathways. We found 10 hub genes and four core genes (FZD6, FZD8, CDK2, and RBBP8) that are strongly linked to OC. Conclusion: This study sheds light on the molecular pathogenesis of OC and is expected to provide potential molecular biomarkers that are beneficial for the treatment and clinical molecular diagnosis of OC. © 2019 Kumar, Kumar, Siva, Doss and Zayed.