Structural Information and Computational Methods Used in Design of Neuraminidase Inhibitors

Sangma, Chak; Hannongbua, Supa

doi:10.2174/157340907780809525

Cited by 6 publications

(4 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, even without any success, the method of extracting natural products from plants, in an attempt to find unidentified compounds for drug activity testing still continues today as a standard procedure in Thailand. Only recently, in silico screening and multidisciplinary approaches in drug discovery were introduced and performed in Thailand [12][13][14][15][16].…”

Section: Computer-aided Drug Discovery From Thai Traditional Knowledgementioning

confidence: 99%

Computer Techniques for Drug Development from Thai Traditional Medicine

Sangma

Chuakheaw²,

Jonkon³

et al. 2010

CPD

Self Cite

View full text Add to dashboard Cite

Thailand has a vast number of plant species. Up to 3000 of them are believed by traditional Thai medicine to possess some biological activity with which researchers have attempted for many years to identify and formulate new drugs. Many chemical compounds from Thai plant species are identified and tested for biological activity that may enable them to be declared lead compounds in drug discovery. Modern methods of drug discovery are rarely used to rationalize and speed-up the process. Within this decade, the first structural database of Thai medicinal plants, Chemiebase, has been built as a platform for virtual screening, using knowledge from Thai traditional medicine. Although this effort is a promising protocol which can be used to validate Thai traditional medicine, there exists another problem that should be resolved before proceeding: It is almost impossible to trace the knowledge to its primary source. Thai traditional knowledge has been passed on orally or - less frequently - in ancient texts. We have built another database, the Thai Herbal Repository Access Initiative (THRAI) database, in order to compile the traditional knowledge into electronic format suitable for the drug design process. Three examples using data from these databases and other computer-aided drug discovery methods to rationalize Thai traditional medicine are presented here, starting with virtual screening exercised on anti-HIV-1 reverse transcriptase, anti-HIV-1 protease, anti-influenza A neuraminidase, and anti-cyclooxygenase (COX), candidates. The second example consists of the use of molecular modeling to propose drug mechanism for anti-tumor compounds. The last one is the study on toxicity assessment of some compounds from Thai medicinal plants.

show abstract

Section: Computer-aided Drug Discovery From Thai Traditional Knowledgementioning

confidence: 99%

Computer Techniques for Drug Development from Thai Traditional Medicine

Sangma

Chuakheaw²,

Jonkon³

et al. 2010

CPD

Self Cite

View full text Add to dashboard Cite

show abstract

“…The conservation of the active site of the influenza virus neuraminidase presents an attractive target for broadspectrum anti-influenza drug design. Over the last two decades several potent and specific inhibitors have been developed (Sangma & Hannongbua, 2007;Liu et al, 2007). The availability of crystal structures of inhibitor-neuraminidase complexes (Bossart-Whitaker et al, 1993;Burmeister et al, 1992Burmeister et al, , 1993Finley et al, 1999;Jedrzejas, Singh, Brouillette, Laver et al, 1995;Lommer et al, 2004;Smith et al, 2001Smith et al, , 2002Sudbeck et al, 1997;Taylor et al, 1998;Varghese & Colman, 1991;Varghese et al, 1992Varghese et al, , 1995Varghese et al, , 1997Varghese et al, , 1998Wang et al, 2005;White et al, 1995) now allows detailed analysis of the structural basis of inhibition.…”

Section: Description Of the Enzymementioning

confidence: 99%

Combining crystallographic information and an aspherical-atom data bank in the evaluation of the electrostatic interaction energy in an enzyme–substrate complex: influenza neuraminidase inhibition

Dominiak

Volkov

Dominiak

et al. 2009

Acta Crystallogr D Biol Cryst

View full text Add to dashboard Cite

Although electrostatic interactions contribute only a part of the interaction energies between macromolecules, unlike dispersion forces they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In the reported study, a wide range of complexes of influenza neuraminidases with inhibitor molecules (sialic acid derivatives and others) have been analyzed using charge densities from a transferable aspherical-atom data bank. The strongest interactions of the residues are with the acidic group at the C2 position of the inhibitor ( approximately -300 kJ mol(-1) for -COO(-) in non-aromatic inhibitors, approximately -120-210 kJ mol(-1) for -COO(-) in aromatic inhibitors and approximately -450 kJ mol(-1) for -PO(3)(2-)) and with the amino and guanidine groups at C4 ( approximately -250 kJ mol(-1)). Other groups contribute less than approximately 100 kJ mol(-1). Residues Glu119, Asp151, Glu227, Glu276 and Arg371 show the largest variation in electrostatic energies of interaction with different groups of inhibitors, which points to their important role in the inhibitor recognition. The Arg292-->Lys mutation reduces the electrostatic interactions of the enzyme with the acidic group at C2 for all inhibitors that have been studied (SIA, DAN, 4AM, ZMR, G20, G28, G39 and BCZ), but enhances the interactions with the glycerol group at C6 for inhibitors that contain it. This is in agreement with the lower level of resistance of the mutated virus to glycerol-containing inhibitors compared with the more hydrophobic derivatives.

show abstract

“…Neuraminidase is the surface protein of the influenza virus 1 . Vaccines against the influenza virus are inactive due its rapid emergence of viral mutagens and thus it paves an immense need for design and synthesis of novel potent sialidase antiviral inhibitor 2 .…”

Section: Introductionmentioning

confidence: 99%

Ab Initio and DFT Investigation of Effect of Substituent at the C7 Position of 4 Amino Sialidase Inhibitor

Krishnan¹

2022

Int J Life Sci Pharm Res

View full text Add to dashboard Cite

Sialic acid is the active site of neuraminidase protein, eventually it cleaves form its substrate via sialsyl cation intermediate and proliferates the viral infection to other cells. On account of weak binding affinity between substrate and receptor, the viral infection communicates to other cells and leads to mortality of humans. DANA is the first sialidase inhibitor formed by the dehydration of the C2 hydroxyl group of sialic acid. The replacement of hydroxyl group at C4 position of DANA by an amino group drastically increases the binding affinity and results 4-amino-DANA inhibitor, which is potent than parent DANA. Crystal structure of DANA shows that several binding sites remain free and it should be explored for more powerful sialidase inhibitors. The current study systematically investigates the effect of substituent on the C7 position of 4-amino-DANA in gas phase and solvent phase as well. X-Ray crystallographic study reveals that the C7 of glycerol side chain remains free. Hence, substituent effect at C7 analysis is carried in search of potent sialidase inhibitors. The abinitio and DFT investigation reveals that guanidinoand methyl group at C7 position drastically increases the binding affinity between substrate and receptor. Hence further investigation of methyl and guanidine derivatives of the 4-amino-DANA could act as a promising candidate for the design and development of sialidase inhibitors. Vaccination for the H1N1 is not effective due to the new viral mutagenic strains and hence, it cannot contain the viral infection.Therefore antiviral drugs will address the limitation of vaccination. The current finding of sialidase antiviral inhibitors will effectively contain the viral infection and prevent the morbidit

show abstract

Structural Information and Computational Methods Used in Design of Neuraminidase Inhibitors

Cited by 6 publications

References 41 publications

Computer Techniques for Drug Development from Thai Traditional Medicine

Computer Techniques for Drug Development from Thai Traditional Medicine

Combining crystallographic information and an aspherical-atom data bank in the evaluation of the electrostatic interaction energy in an enzyme–substrate complex: influenza neuraminidase inhibition

Ab Initio and DFT Investigation of Effect of Substituent at the C7 Position of 4 Amino Sialidase Inhibitor

Contact Info

Product

Resources

About