Pesticides in mixture disrupt metabolic regulation: In silico and in vivo analysis of cumulative toxicity of mancozeb and imidacloprid on body weight of mice

2014 ◽  
Vol 205 ◽  
pp. 226-234 ◽  
Author(s):  
Rakesh Bhaskar ◽  
Banalata Mohanty
Keyword(s):  
Body Weight ◽  
In Silico ◽  
Metabolic Regulation ◽  
Cumulative Toxicity ◽  
In Vivo Analysis

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals Modulation of HIF-2α PAS-B domain contributes to physiological responses

2018 ◽  
Vol 115 (52) ◽  
pp. 13240-13245 ◽  
Author(s):  
Zhihui Feng ◽  
Xuan Zou ◽  
Yaomin Chen ◽  
Hanzhi Wang ◽  
Yingli Duan ◽  
...  
Keyword(s):  
Body Weight ◽  
Metabolic Regulation ◽  
Body Weight Gain ◽  
Metabolic Stress ◽  
Vital Role ◽  
Mutant Mice ◽  
Single Mutation ◽  
Wild Type ◽  
Adipose Mass

Hypoxia-inducible factors (HIFs) are transcription factors in the basic helix–loop–helix PER-ARNT-SIM (bHLH-PAS) protein family that contain internal hydrophobic cavities within their PAS-A and PAS-B domains. Among HIFs, the HIF-2α PAS-B domain contains a relatively large cavity exploited for the development of specific artificial ligands such as PT2399. Administration of PT2399 could suppress HIF-2α target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2α PAS-B domain suppressed HIF-2α activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF-2α hypoxia response. In contrast, the mutant mice did not phenocopy PT2399 intervention in wild-type mice under metabolic stress. Under a high-fat diet (HFD), the mutant mice exert enhanced adipogenesis and obtain larger adipose mass and body weight gain compared to wild type. However, administration of PT2399 along with HFD feeding sufficiently suppressed HFD-induced body weight and adipose mass increase through suppression of adipogenesis and lipogenesis. The accompanying decreased lipid accumulation in the liver and improved glucose tolerance in wild-type mice were not observed in the mutant mice indicating negative regulation of HIF-2α on obesity and a complex role for the PAS-B domain in metabolic regulation. Notably, short-term administration of PT2399 to obese mice decreased adipose mass and improved metabolic condition. These results indicate a regulatory role for HIF-2α in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders.

In-Silico Analysis to Identify Potential Inhibitors Against the Protein NSP12 of SARS-CoV-2

2021 ◽  
Vol 6 (3) ◽  
pp. 48-60
Author(s):  
Hima Vyshnavi ◽  
Gayathri S. S. ◽  
Shahanas Naisam ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
In Silico ◽  
Interaction Analysis ◽  
In Silico Analysis ◽  
Drug Efficacy ◽  
Drug Candidate ◽  
In Vivo Analysis ◽  
The Stability ◽  
Potential Inhibitors ◽  
Silico Analysis

In this pandemic condition, a drug candidate which is effective against COVID-19 is very much desired. This study initiates an in silico analysis to screen small molecules such as phytochemicals, drug metabolites, and natural metabolites against Nsp12 (a catalytic unit for RNA transcription and replication). Molecular interaction analysis of 6M71 was carried out against 2,860 ligands using Schrodinger Glide software. After docking analysis, the top 10 molecules (Glide score) were subjected to MD simulation for validating the stability. It resulted in top 10 compounds with high binding affinities with the target molecule NSP 12. Out of these, top 3 compounds including PSID_08_LIG3 (HMDB0133544), PSID_08_LIG4 (HMDB0132898), and PSID_08_LIG9 (HMDB0128199) show better Glide scores, better H-bond interaction, better MMGBSA value and stability on dynamic simulation after analysis of the results. The suggested ligands can be postulated as effective antiviral drugs against COVID-19. Further in vivo analysis is needed for validating the drug efficacy.

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