Aged population and immunocompromised patients: impact on SARS-CoV-2 variants and treatment outcomes

Patients with an immunocompromised state are at risk of developing a long-term infection from the coronavirus 2 that causes severe acute respiratory syndrome (SARS-CoV-2) [...

A NOVEL QSAR MODEL FOR EVALUATING AND PREDICTING THE INHIBITION ACTIVITY OF H1-RECEPTOR ANTAGONISTS: A SERIES OF THIENOPYRIMIDINE DERIVATIVES

ABSTRACT A Quantitative Structure Activity Relationship (QSAR) study has been established using combination of most influencing physiochemical parameters viz. thermodynamic, electronic, geometric & quantum mechanical descriptors, and H1-antihistaminic activity of a series of thienopyrimidines, the novel Histamine H1 receptor antagonists. Genetic function approximation (GFA) technique was used to identify the descriptors that have influence on biological activity. Dipole, AlogP 98, Jurs and LUMO descriptors were found to influence biological activity significantly. Lipophilicity of compounds was found to have a significant role in H1 Histaminic inhibition along with other thermodynamic, spatial and electronic descriptors. Positive contribution of Dipole, AlogP 98 descriptors suggests that molecules with lipophilic-electronic substituents are more likely to improve the potency. Developed models were found to be significant and predictive as evidenced from their internal and external cross-validation statistics.   Keywords: H1-receptor antagonists; thienopyrimidines; molecular descriptor; genetic function approximations; cross-validation; quantitative structure activity relationship Abbreviations: QSAR : Quantitative structure activity relationship GFA    : Genetic function approximation LOF    : Friedman’s lack of fit VIF     : Variance inflation factor Â

The analog of cGAMP, c-di-AMP, activates STING mediated cell death pathway in estrogen-receptor negative breast cancer cells

Immune adaptor protein like STING/MITA regulate innate immune response and plays a critical role in inflammation in the tumor microenvironment and regulation of metastasis including breast cancer. Chromosomal instability in highly metastatic cells releases fragmented chromosomal parts in the cytoplasm, hence the activation of STING via an increased level of cyclic dinucleotides (cDNs) synthesized by cGMP-AMP synthase (cGAS). Cyclic dinucleotides 2’ 3’-cGAMP and it's analog can potentially activate STING mediated pathways leading to nuclear translocation of p65 and IRF-3 and transcription of inflammatory genes. The differential modulation of STING pathway via 2’ 3’-cGAMP and its analog and its implication in breast tumorigenesis is still not well explored. In the current study, we demonstrated that c-di-AMP can activate type-1 IFN response in ER negative breast cancer cell lines which correlate with STING expression. c-di-AMP binds to STING and activates downstream IFN pathways in STING positive metastatic MDA-MB-231/MX-1 cells. Prolonged treatment of c-di-AMP induces cell death in STING positive metastatic MDA-MB-231/MX-1 cells mediated by IRF-3. c-di-AMP induces IRF-3 translocation to mitochondria and initiates Caspase-9 mediated cell death and inhibits clonogenicity of triple-negative breast cancer cells. This study suggests that c-di-AMP can activate and modulates STING pathway to induce mitochondrial mediated apoptosis in estrogen-receptor negative breast cancer cells

Identification of some novel pyrazolo[1,5-<i>a</i>]pyrimidine derivatives as InhA inhibitors through pharmacophore-based virtual screening and molecular docking

<p>The InhA inhibitors play key role in mycolic acid synthesis by preventing the fatty acid biosynthesis pathway. In this present article, Pharmacophore modelling and molecular docking study followed by <i>in silico</i> virtual screening could be considered as effective strategy to identify newer enoyl-ACP reductase inhibitors. Pyrrolidine carboxamide derivatives were opted to generate pharmacophore models using HypoGen algorithm in Discovery studio 2.1. Further it was employed to screen Zinc and Minimaybridge databases to identify and design newer potent hit molecules. The retrieved newer hits were further evaluated for their drug likeliness and docked against enoyl acyl carrier protein reductase. Here, novel pyrazolo[1,5-<i>a</i>]pyrimidine analogues were designed and synthesized with good yields. Structural elucidation of synthesized final molecules was perform through IR, MASS, ¹H-NMR, ¹³C-NMR spectroscopy and further tested for its <i>in vitro</i> anti-tubercular activity against H37Rv strain using Microplate Alamar blue assay (MABA) method. Most of the synthesized compounds displayed strong anti-tubercular activities. Further, these potent compounds were gauged for MDR-TB, XDR-TB and cytotoxic study.</p

Molecular docking, QSAR and ADMET based mining of natural compounds against prime targets of HIV

<p>AIDS is one of the multifaceted diseases and this underlying complexity hampers its complete cure. The toxicity of existing drugs and emergence of multidrug-resistant virus makes the treatment worse. Development of effective, safe and low-cost anti-HIV drugs is among the top global priority. Exploration of natural resources may give ray of hope to develop new anti-HIV leads. Among the various therapeutic targets for HIV treatment, reverse transcriptase, protease, integrase, GP120, and ribonuclease are the prime focus. In the present study, we predicted potential plant-derived natural molecules for HIV treatment using computational approach, i.e. molecular docking, quantitative structure activity relationship (QSAR), and ADMET studies. Receptor-ligand binding studies were performed using three different software for precise prediction – Discovery studio 4.0, Schrodinger and Molegrow virtual docker. Docking scores revealed that Mulberrosides, Anolignans, Curcumin and Chebulic acid are promising candidates that bind with multi targets of HIV, while Neo-andrographolide, Nimbolide and Punigluconin were target-specific candidates. Subsequently, QSAR was performed using biologically proved compounds which predicted the biological activity of compounds. We identified Anolignans, Curcumin, Mulberrosides, Chebulic acid and Neo-andrographolide as potential natural molecules for HIV treatment from results of molecular docking and 3D-QSAR. <i>In silico</i> ADMET studies showed drug-likeness of these lead molecules. Structure similarities of identified lead molecules were compared with identified marketed drugs by superimposing both the molecules. Using <i>in silico</i> studies, we have identified few best fit molecules of natural origin against identified targets which may give new drugs to combat HIV infection after wet lab validation.</p

Advanced Computational Methodologies Used in the Discovery of New Natural Anticancer Compounds

Natural chemical compounds have been widely investigated for their programmed necrosis causing characteristics. One of the conventional methods for screening such compounds is the use of concentrated plant extracts without isolation of active moieties for understanding pharmacological activity. For the last two decades, modern medicine has relied mainly on the isolation and purification of one or two complicated active and isomeric compounds. The idea of multi-target drugs has advanced rapidly and impressively from an innovative model when first proposed in the early 2000s to one of the popular trends for drug development in 2021. Alternatively, fragment-based drug discovery is also explored in identifying target-based drug discovery for potent natural anticancer agents which is based on well-defined fragments opposite to use of naturally occurring mixtures. This review summarizes the current key advancements in natural anticancer compounds; computer-assisted/fragment-based structural elucidation and a multi-target approach for the exploration of natural compounds