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1.
J Biomol Struct Dyn ; 41(8): 3265-3280, 2023 05.
Article in English | MEDLINE | ID: mdl-35257637

ABSTRACT

Being highly transmissible, severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected millions of people causing devastating global impact and has also not slowed down even after vaccination. The emerges of new strains has made more concerns than the original one. We need a new therapeutic approach against the disease. Our comprehensive in silico study investigates dual herbal combinatorial methanolic extracts of W. somnifera (W) alone and with P. emblica (P) (W:P/1:4) , T. sinensis (T) (W:T/1:4), B. monnieri (B) (W:B/1:1), O. basilicum (O) (W:O/1:4), A. racemosus (A) (W:A/4:1) for potential four phytochemicals as ligands docked with eight COVID-19 Nonstructural proteins (nsp)-main protease (PDB ID:6LU7), papain-like protease (6WUU), helicase ADP (2XZL), N7-methyltransferase (5C8S), endoribonuclease (6WLC), 2'O-methyltransferase (6WVN), RNA dependent RNA polymerase (6M71), and 3Cprotease (6YNQ) along with Remdesivir and Hydroxychloroquine. Ligands from W:P/1:4 showed remarkable docking score (-9.01 kcal/mol) 6M71-(8E,11E,14E)-eicosa-8,11,14-trienoicacidmethylester (EIS) and (-9.99 kcal/mol) 6YNQ-N-[(E)-[4-[(2-methoxydibenzofuran-3-yl)amino]-4-oxobutan-2-ylidene]amino] 4nitrobenzamide (MET). Further, MD simulations were studied for 100 ns and showed the complexes were flexible, stable in the binding pockets of the receptors, and MM-PBSA analysis determined high binding energy of -129.673 ± 15.284 and -134.594 ± 7.085 for 6M71-EIS (Asn496, Lys577, Arg569) and 6YNQ-MET (Cys145, His41). Finally, in vitro JURKAT E6.1 cell lines treated with W:P/1:4 and W:O/1:4 methanolic extracts yielded 44.06 and 31.53 ng/mL levels for interferon alpha to counteract an external stimulus by establishing an antiviral state. Thus, nsp is targeted to design effective antiviral drugs for developing an effective therapeutic approach to combat viral RNA synthesis, processing, and suppression of host immunity.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Withania , Humans , SARS-CoV-2 , Antiviral Agents/pharmacology , Methanol , Methyltransferases , Papain , Peptide Hydrolases
2.
Biomed Res Int ; 2022: 6600403, 2022.
Article in English | MEDLINE | ID: mdl-35860806

ABSTRACT

Streptomyces is amongst the most amenable genera for biotechnological applications, and it is extensively used as a scaffold for drug development. One of the most effective therapeutic applications in the treatment of cancer is targeted therapy. Small molecule therapy is one of them, and it has gotten a lot of attention recently. Streptomyces derived compounds namely streptenols A, C, and F-I and streptazolin were subjected for ADMET property assessment. Our computational studies based on molecular docking effectively displayed the synergistic effect of streptomyces-derived compounds on the gynecological cancer target PIK3CA. These compounds were observed with the highest docking scores as well as promising intermolecular interaction stability throughout the molecular dynamic simulation. Molecular docking and molecular dynamic modeling techniques were utilized to investigate the binding mode stability of drugs using a pharmacophore scaffold, as well as physicochemical and pharmacokinetic aspects linked to alpelisib. With a root mean square fluctuation of the protein backbone of less than 0.7 nm, they demonstrated a steady binding mode in the target binding pocket. They have also prompted hydrogen bonding throughout the simulations, implying that the chemicals have firmly occupied the active site. A comprehensive study showed that streptenol D, streptenol E, streptenol C, streptenol G, streptenol F, and streptenol B can be considered as lead compounds for PIK3CA-based inhibitor design. To warrant the treatment efficacy against cancer, comprehensive computational research based on proposed chemicals must be assessed through in vitro studies.


Subject(s)
Neoplasms , Streptomyces , Class I Phosphatidylinositol 3-Kinases , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation
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