Supervisors info:
Θωμάς Μαυρομούστακος, Καθηγητής, Τμήμα Χημείας, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
The aim of the present thesis was the in silico identification of new compounds against the influenza A virus.
Influenza A virus is one of the most common causes of respiratory infections in humans, which may take the form of a pandemic with increased mortality rates. Amantadine was discovered in the 1960s, it was the first amino-adamantan analogue used as an ion channel inhibitor of the membrane protein M2. Rimantadine was used in the 1980s. Since the decade of 2010, the emergence of mutations, particularly the S31N mutation, has prompted resistance to these drugs, resulting in the finding of new conjugates of amantadine compounds with a polar head becoming an interesting field of research. Currently, neuraminidase inhibitors are the only class of drugs available. An intense research effort by some groups has resulted in finding the structure of compound conjugates composed of amantadine and usually a polar heterocycle linked to a methylene bridge. These compounds were active against wild type viruses (wild type, WT) and mutant S31N. The sample of these compounds and wild-type virus activities were used in the present study to control the design of novel compounds against the wild-type influenza A virus.
In the present study a combination of molecular binding with 3D dimensional structure-action relationships (3D-QSAR) was attempted to find new, improved conjugates of polar head amantadine compounds as inhibitors of the wild type of influenza A virus. Structure-based ligand-based drug design, where two validated 3D-QSAR CoMFA and CoMSIA models emerged. Firstly, energy minimization of 38 conjugates of compounds was performed between an amino-adamantane derivative and a heterocyclic molecule. These compounds are inhibitors of the ion channel M2/WT. Secondly, alignment of derivatives and creation of the CoMFA and CoMSIA fields was carried out. Finally, two validated 3D-QSAR CoMFA and CoMSIA models were created. The workflow followed gave us information on the structural characteristics that an ion-channel blocker of the M2 / WT protein must bring. The silico-derived models were used to predict biological activity of new polar head amantadine compound conjugates comprising amantadine attached to a polar group.
Results from in silico studies confirmed the in vitro influenza A/WT virus inhibition experiments from the new derivatives. Furthermore, the synthesis of R enantiomers is proposed as they are expected to exhibit greater biological activity against the Influenza A WT virus.
Keywords:
Influenza A Virus, Molecular Modeling, 3D-QSAR, CoMFA/CoMSIA
