Non-small cell lung cancer (NSCLC) has evolved into the deadliest in the present scenario. The progression of NSCLC is mainly due to the dysregulation of the tyrosine kinase family's epidermal growth factor receptor (EGFR). Thus, EGFR has been widely studied as a major target in the treatment of NSCLC, but the lack of selectivity and drug resistance limit the use of existing therapeutic agents. Considering the urgent necessity for the advanced development of EGFR inhibitors, we have implemented a three-dimensional structure-activity relationship (3D QSAR), molecular docking, and MMGBSA studies on a series of pyrimidine derivatives. In the 3D QSAR, the comparative molecular field analysis model (CoMFA) was obtained with a correlation coefficient (r<sup>2</sup>) = 0.698, cross-validated correlation coefficient (q<sup>2</sup>) = 0.541, and predictive r<sup>2</sup> (r<sup>2</sup><sub>pred</sub>) = 0.509. The comparative molecular similarity indices analysis (CoMSIA) model also displayed similar results with r<sup>2 </sup>= 0.72, q<sup>2 </sup>= 0.586, and r<sup>2</sup><sub>pred</sub>= 0.495. The statistical parameters fulfill the acceptability criteria of the models. Docking studies revealed the binding interactions of the pyrimidine derivatives with double mutant EGFR<sup>L858R/T790M</sup>. Docking scores of the top two selected compounds 29 and 34 were 92.99 and 92.13, respectively. Analyzing 3D QSAR contour plots and docking results reviewed some important structural attributes of EGFR <sup>L858R/T790M</sup> selective inhibitors, which directed the designing of some new molecules. The designed compounds showed good predictive activity and exhibited higher binding interactions with EGFRL858R/T790M than the reference ligand gefitinib. Moreover, to evaluate the binding of selected top hits from docking and designed compounds, MMGBSA (Molecular Mechanics-Generalized Born Surface Area) analysis was performed, which revealed that the designed compound (N7) showed a good binding affinity with EGFR<sup>L858R/T790M</sup> (dG = -68.59 kcal/mol) as compared to other compounds. Further, in silico ADME predictions revealed the drug-likeness of the designed compounds. Thus, this work will guide researchers in future developments of pyrimidine derivatives as EGFR inhibitors.
Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) main protease (MPro) is recognized as an important therapeutic target protein in the drug development for COVID-19. To date, clinical trials of many vaccine and other viral protease inhibitors (PI) are currently under investigation. Undoubtedly, there are chances of possible side effects and ineffectiveness. Thus, the search for natural bio-active molecules is of great interest that will exert antiviral activity as well as have least chances of toxicity. Fungi are considered as bio-enriched source of producing antiviral compounds. This study is focused on identifying potential fungal derived antiviral molecules with good binding affinity against SARS-CoV-2 MPro using molecular docking. Semicochliodinol B was identified as the best lead molecule with higher binding affinity ([Formula: see text][Formula: see text]kcal/mol) as compared to the co-crystalized ligand ([Formula: see text][Formula: see text]kcal/mol). The results of molecular docking confirm the hydrogen bond interaction of Semicochliodinol B with Glu166 and Asn142 as well as hydrophobic interactions with 20 amino acid residues of SARS-CoV-2 MPro. Semicochliodinol B also exhibited good binding affinity against SARS-CoV MPro and Middle east respiratory syndrome-related corona virus (MERS-CoV MPro), suggesting its broad-spectrum activity. Druglikeness, Absorption, distribution, metabolism, excretion (ADME) and toxicity studies also directed that Semicochliodinol B may become a promising drug candidate and thus it can be further investigated as a potential inhibitor of SARS-CoV-2 MPro.
Frequent mutation and variable immunological protection against vaccination is a common feature for COVID-19 pandemic. Early detection and confinement remain key to controlling further spread of infection. In response, we have developed an aptamer-based system that possesses both diagnostic and therapeutic potential towards the virus. A random aptamer library (~ 1017 molecules) was screened using systematic evolution of ligands by exponential enrichment (SELEX) and aptamer R was identified as a potent binder for the SARS-CoV-2 spike receptor binding domain (RBD) using in vitro binding assay. Using a pseudotyped viral entry assay we have shown that aptamer R specifically inhibited the entry of a SARS-CoV-2 pseudotyped virus in HEK293T-ACE2 cells but did not inhibit the entry of a Vesicular Stomatitis Virus (VSV) glycoprotein (G) pseudotyped virus, hence establishing its specificity towards SARS-CoV-2 spike protein. The antiviral potential of aptamers R and J (same central sequence as R but lacking flanked primer regions) was tested and showed 95.4% and 82.5% inhibition, respectively, against the SARS-CoV-2 virus. Finally, intermolecular interactions between the aptamers and the RBD domain were analyzed using in silico docking and molecular dynamics simulations that provided additional insight into the binding and inhibitory action of aptamers R and J.
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