Molecular modeling and lead design of substituted zanamivir derivatives as potent anti-influenza drugs.
BACKGROUND
Influenza virus spreads infection by two main surface glycoproteins, namely hemagglutinin (HA) and neuraminidase (NA). NA cleaves the sialic acid receptors eventually releasing newly formed virus particles which then invade new cells. Inhibition of NA could limit the replication of virus to one round which is insufficient to cause the disease.


RESULTS
An experimentally reported series of acylguanidine zanamivir derivatives was used to develop GQSAR model targeting NA in different strains of influenza virus, H1N1 and H3N2. A combinatorial library was developed and their inhibitory activities were predicted using the GQSAR model.


CONCLUSIONS
The top leads were analyzed by docking which revealed the binding modes of these inhibitors in the active site of NA (150-loop). The top compound (AMA) was selected for carrying out molecular dynamics simulations for 15 ns which provided insights into the time dependent dynamics of the designed leads. AMA possessed a docking score of -8.26 Kcal/mol with H1N1 strain and -7.00 Kcal/mol with H3N2 strain. Ligand-bound complexes of both H1N1 and H3N2 were observed to be stable for 11 ns and 7 ns respectively. ADME descriptors were also calculated to study the pharmacokinetic properties of AMA which revealed its drug-like properties.
Department of Biotechnology, Delhi Technological University, New Delhi, 110042, India.
Dhwani
D
Dholakia
Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, 304022, India.
Sukriti
S
Goyal
Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan, 304022, India.
Salma
S
Jamal
Department of Biotechnology, TERI University, New Delhi, 110070, India.
Aditi
A
Singh
Department of Biotechnology, Delhi Technological University, New Delhi, 110042, India.
Asmita
A
Das
School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India. abhinavgr@gmail.com.
Abhinav
A
Grover
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000201:enzymology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000201:enzymology; D007251:Influenza, Human / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053243:Zanamivir / Q000737:chemistry / Q000494:pharmacology*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir
H1N1; H3N2; Influenza; NA; Neuraminidase; QSAR