In silico studies of alkaloids and their derivatives against N-acetyltransferase EIS protein from Mycobacterium tuberculosis.

Antibiotic resistance against Mycobacterium tuberculosis (M.tb.) has been a significant cause of death worldwide. The Enhanced intracellular survival (EIS) protein of the bacteria is an acetyltransferase that multiacetylates aminoglycoside antibiotics, preventing them from binding to the bacterial ribosome. To overcome the EIS-mediated antibiotics resistance of M.tb., we compiled 888 alkaloids and derivatives from five different databases and virtually screened them against the EIS receptor. The compound library was filtered down to 87 compounds, which underwent additional analysis and filtration. Moreover, the top 15 most prominent phytocompounds were obtained after the drug-likeness prediction and ADMET screening. Out of 15, nine compounds confirmed the maximum number of hydrogen bond interactions and reliable binding energies during molecular docking. Additionally, the Molecular dynamics (MD) simulation of nine compounds showed the three most stable complexes, further verified by re-docking with mutated protein. The density functional theory (DFT) calculation was performed to identify the HOMO-LUMO energy gaps of the selected three potential compounds. Finally, our selected top lead compounds i.e., Alkaloid AQC2 (PubChem85634496), Nobilisitine A (ChEbi68116), and N-methylcheilanthifoline (ChEbi140673) demonstrated more favourable outcomes when compared with reference compounds (i.e., 39b and 2i) in all parameters used in this study. Therefore, we anticipate that our findings will help to explore and develop natural compound therapy against multi and extensively drug-resistant strains of M.tb.Communicated by Ramaswamy H. Sarma.

Immunoregulatory framework and the role of miRNA in the pathogenesis of NSCLC - A systematic review.

With a 5-year survival rate of only 15%, non-small cell lung cancer (NSCLC), the most common kind of lung carcinoma and the cause of millions of deaths annually, has drawn attention. Numerous variables, such as disrupted signaling caused by somatic mutations in the EGFR-mediated RAS/RAF/MAPK, PI3K/AKT, JAK/STAT signaling cascade, supports tumour survival in one way or another. Here, the tumour microenvironment significantly contributes to the development of cancer by thwarting the immune response. MicroRNAs (miRNAs) are critical regulators of gene expression that can function as oncogenes or oncosuppressors. They have a major influence on the occurrence and prognosis of NSCLC. Though, a myriad number of therapies are available and many are being clinically tested, still the drug resistance, its adverse effect and toxicity leading towards fatality cannot be ruled out. In this review, we tried to ascertain the missing links in between perturbed EGFR signaling, miRNAs favouring tumorigenesis and the autophagy mechanism. While connecting all the aforementioned points multiple associations were set, which can be targeted in order to combat NSCLC. Here, we tried illuminating designing synthetically engineered circuits with the toggle switches that might lay a prototype for better therapeutic paradigm.

Anthraquinolone and quinolizine derivatives as an alley of future treatment for COVID-19: an in silico machine learning hypothesis.

Coronavirus disease 2019 (Covid-19), caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has come to the fore in Wuhan, China in December 2019 and has been spreading expeditiously all over the world due to its high transmissibility and pathogenicity. From the outbreak of COVID-19, many efforts are being made to find a way to fight this pandemic. More than 300 clinical trials are ongoing to investigate the potential therapeutic option for preventing/treating COVID-19. Considering the critical role of SARS-CoV-2 main protease (Mpro) in pathogenesis being primarily involved in polyprotein processing and virus maturation, it makes SARS-CoV-2 main protease (Mpro) as an attractive and promising antiviral target. Thus, in our study, we focused on SARS-CoV-2 main protease (Mpro), used machine learning algorithms and virtually screened small derivatives of anthraquinolone and quinolizine from PubChem that may act as potential inhibitor. Prioritisation of cavity atoms obtained through pharmacophore mapping and other physicochemical descriptors of the derivatives helped mapped important chemical features for ligand binding interaction and also for synergistic studies with molecular docking. Subsequently, these studies outcome were supported through simulation trajectories that further proved anthraquinolone and quinolizine derivatives as potential small molecules to be tested experimentally in treating COVID-19 patients.

Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1.

Conserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.