scholarly journals Molecular docking approach to elucidate metabolic detoxification pathway of polycyclic aromatic hydrocarbons

2021 ◽  
pp. 150-161
Author(s):  
Mohammad Kalim Ahmad Khan ◽  
Salman Akhtar ◽  
Fahad Al-Khodairy
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Aromatic Hydrocarbons ◽  
Glutathione S Transferase ◽  
Drug Discovery And Development ◽  
Docking Approach ◽  
Polycyclic Aromatic ◽  
Metabolic Detoxification ◽  
Free Energy Of Binding ◽  
Detoxification Pathway

This study assessed the molecular interactions of (±)-anti-and-syn- dibenzo[a,l]pyrene-11,12-diol-13,14-epoxide (DBPDE), 7,12- dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (DMBADE), N2- hydroxylated-PhIP(N2-OH-PhIP), (±)-anti-and-syn-benzo[a]pyrene-7,8-diol- 9,10-epoxide (BPDE) with various Glutathione S-transferase (GST) and N- acetyltransferase (NAT) isozymes. Our in-silico data revealed that GSTP1 (- 8.83 kcal/mol), showing more plausible binding as compared to GSTM1 (-8.74 kcal/mol) and GSTA1 (ΔG: -8.03 kcal/mol) against (-)-anti-DBPDE and (+)- syn-DBPDE. We also investigated the involvement of GST and NAT isozymes in the conjugation of DMBADE andN2-OH-PhIP as a control despite their preferred routes sulfonation and glucuronidation for detoxification. The findings exhibited feeble binding of different classes of GSTs with metabolites of DMBA and PhIP, as highlighted by their free energy of binding. The enzymatic activity of GSTM1 against the most potent diol-epoxide of benzo[a]pyrene (BP), (+)-anti-BPDE, and (+)-syn-BPDE followed by GSTP1 and GSTA1 has well documented. In addition, these findings provide new perspectives for most probable mechanistic details of the detoxification pathway of PAHs and xenobiotics useful in combination therapy for future ligand-based drug discovery and development.

Development of Xanthine Based Inhibitors Targeting Phosphodiesterase 9A

2017 ◽  
Vol 14 (10) ◽  
pp. 1122-1137 ◽  
Author(s):  
Nivedita Singh ◽  
Parameswaran Saravanan ◽  
M.S. Thakur ◽  
Sanjukta Patra
Keyword(s):  
Free Energy ◽  
Active Site ◽  
Signal Transduction Pathway ◽  
Docking Study ◽  
Primary Objective ◽  
Cgmp Level ◽  
Active Site Residues ◽  
Aromatic Fragment ◽  
Docking Approach ◽  
Free Energy Of Binding

Background: Phosphodiesterases 9A (PDE9A) is one of the prominent regulating enzymes of the signal transduction pathway having highest catalytic affinity for second messenger, cGMP. When the cGMP level is lowered, an uncontrolled expression of PDE9A may lead to various neurodegenerative diseases. To regulate the catalytic activity of PDE9A, potent inhibitors are needed. Objective: The primary objective of the present study was to develop new xanthine based inhibitors targeting PDE9A. This study was an attempt to bring structural diversification in PDE9A inhibitor development because most of the existing inhibitors are constructed over pyrazolopyrimidinone scaffold. Methods: Manual designing and parallel molecular docking approach were used for the development of xanthine derivatives. In this study, N1, N3, N9 and C8 positions of xanthine scaffold were selected as substitution sites to design 200 new compounds. Reverse docking and pharmaceutical analyses were used for final validation of most promising compounds. Results: By keeping free energy of binding cut-off of -6.0 kcal/mol, 52 compounds were screened. The compounds with substitution at N1, N3 and C8 positions of xanthine showed good occupancy in PDE9A active site pocket with a significant interaction pattern. This was further validated by screening different factors such as free energy of binding, inhibition constant and interacting active site residues in the 5Å region. Substitution at C8 position with phenyl substituent determined the inhibition affinity of compounds towards PDE9A by establishing a strong hydrophobic - hydrophobic interaction. The alkyl chain at N1 position generated selectivity of compounds towards PDE9A. The aromatic fragment at N3 position increased the binding affinity of compounds. Thus, by comparative docking study, it was found that compound 39-42 formed selective interaction towards PDE9A over other members of the PDE superfamily. Conclusion: From the present study, N1, N3 and C8 positions of xanthine were concluded as the best sites for substitution for the generation of potent PDE9A inhibitors.

scholarly journals Investigation of the anti-TB potential of selected alkaloid constituents using molecular docking approach

2020 ◽  
Author(s):  
Mohammad Kawsar Sharif Siam ◽  
Mohammad Umer Sharif Shohan ◽  
Zaira Zafroon
Keyword(s):  
Free Energy ◽  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Protein Binding ◽  
Binding Free Energy ◽  
Chemical Constituents ◽  
Biological Evaluation ◽  
Natural Sources ◽  
Docking Score ◽  
Docking Approach

AbstractMycobacterium tuberculosis, the leading bacterial killer disease worldwide, causes Human tuberculosis (TB). Due to the growing problem of drug resistant Mycobacterium tuberculosis strains, new anti-TB drugs are urgently needed. Natural sources such as plant extracts have long played an important role in tuberculosis management and can be used as a template to design new drugs. A wide screening of natural sources is time consuming but the process can be significantly sped up using molecular docking. In this study, we used a molecular docking approach to investigate the interactions between selected natural constituents and three proteins MtPanK, MtDprE1 and MtKasA involved in the physiological functions of Mycobacterium tuberculosis which are necessary for the bacteria to survive and cause disease. The molecular docking score, a score that accounts for the binding affinity between a ligand and a target protein, for each protein was calculated against 150 chemical constituents of different classes to estimate the binding free energy. The docking scores represent the binding free energy. The best docking scores indicates the highest ligand protein binding which is indicated by the lowest energy value. Among the natural constituents, Shermilamine B showed a docking score of - 8.5kcal/mol, Brachystamide B showed a docking score of −8.6 kcal/mol with MtPanK, Monoamphilectine A showed a score of −9.8kcal/mol with MtDprE1.These three compounds showed docking scores which were superior to the control inhibitors and represent the opportunity of in vitro biological evaluation and anti-TB drug design. Consequently, all these compounds belonged to the alkaloid class. Specific interactions were studied to further understand the nature of intermolecular bonds between the most active ligands and the protein binding site residues which proved that among the constituents monoamphilectine A and Shermilamine B show more promise as Anti-TB drugs. Furthermore, the ADMET properties of these compounds or ligands showed that they have no corrosive or carcinogenic parameters.Graphical Abstract

scholarly journals Identification of DNA gyrase Subunit a Mutations Associated with Ciprofloxacin Resistance in Staphylococcus aureus Isolated from Nasal Infection in Kurdistan-Iran

2017 ◽  
Vol 7 (1) ◽  
pp. 186
Author(s):  
Roya Darbani ◽  
Chiako Farshadfar ◽  
Somayeh Tavana ◽  
Hamidreza Saljoughi ◽  
Sheida Sadat Zonouri
Keyword(s):  
Staphylococcus Aureus ◽  
Free Energy ◽  
Molecular Docking ◽  
Dna Gyrase ◽  
Amino Acid Sequences ◽  
Nucleotide Sequencing ◽  
Molegro Virtual Docker ◽  
Fluoroquinolone Antibiotics ◽  
Ciprofloxacin Resistance ◽  
Free Energy Of Binding

Fluoroquinolone antibiotics such as ciprofloxacin are useful drugs against infections caused by Staphylococcus aureus and mutations in DNA gyrase which control bacterial DNA topology, can be one of the reason of occurrence resistance to this class of antibiotics. Therefore finding new mutations and study of the quinolone interaction with mutated GyrA can provide important issues for explanation resistance. In this study 5 ciprofloxacin resistance Staphylococcus aureus isolated among 50 collected S.aureus strains. By PCR testing, gyrA genes in resistance strains was amplified and nucleotide sequencing was done. Nucleotide sequences translate to amino acid sequences then by blastp homology between each GyrA mutant and reference GyrA were compared and mutations were recognized, at last molecular docking were done for GyrA protein and ciprofloxacin, based on free energy of binding decide if the mutations are responsible of resistance or not. The results show glutamic acid and threonine adjacent to each other in common positions 21-22, 32-33, 65-66, 84-85, 101-102, 106-107, 128-129 and 138-139 in all 5 strains were inserted . In order to finding association between mutations and ciprofloxacin resistance molecular docking by Molegro Virtual Docker 5.5 was done. Free energy of binding between reference GyrA- ciprofloxacin and mutant GyrA- ciprofloxacin were -92.3477 and -73.1642 respectively. We conclude different mutations can be affected structure of GyrA and make ciprofloxacin resistance. Finding these kinds of mutations are important and preventing them is indispensable.

Incorporating replacement free energy of binding-site waters in molecular docking

2014 ◽  
Vol 82 (9) ◽  
pp. 1765-1776 ◽  
Author(s):  
Hanzi Sun ◽  
Lifeng Zhao ◽  
Shiming Peng ◽  
Niu Huang
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Site ◽  
Free Energy Of Binding
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