Antimicrobial and cytotoxic arylazoenamines. Part III: Antiviral activity of selected classes of arylazoenamines

Synergistic experimental/computational studies on arylazoenamine derivatives that target the bovine viral diarrhea virus RNA-dependent RNA polymerase

“…Specifically, for this series of compounds, the mean value of the electrostatic energy (DE EL + DG PB ) is approximately +32 kcal/mol, whilst the corresponding mean values of the van der Waals and hydrophobic overall interaction energies (DE VDW + DG NP ) are À53 kcal/mol, confirming that, in line with several previous findings, the association between the ligands and the RdRp is mainly driven by more favorable nonpolar interactions in the complex than in the solution, in keeping with a proposed general scheme for non-covalent associations. 22,28,31,32,37,38 The calculated changes in solute entropy, ÀTDS, are physically reasonable and confined within a small range of values, an expected results as the major role in determining the overall conformation of these compounds is played by the invariant presence of the rigid aza moiety bound to the aromatic ring. More importantly, it is quite encouraging that the experimental rank of our compound series toward BDVD RdRp is well consistent with our in silico prediction (vide infra for a detailed discussion).…”

“…22 Despite the high toxicity on the host cells often observed for these molecular series, 22 several compounds exhibit EC 50 values comparable with that of the reference drug, NM-108 (EC 50 = 1.7 lM). On the whole, the EC 50 values for 9 of these active principles were determined to be in the sub/micromolar range (0.8-10 lM), 11 compounds had EC 50 between 11 and 30 lM, and only 8 had EC 50 in the range 31-100 lM.…”

“…35,36 Despite the enormous size of the conformational space for a given ligand, current docking methodologies have been successfully employed by our group in reproducing crystallographic evidences as well as to predict putative binding modes. 22,28,31,32,37 However, conformational sampling also plays an important role in calculating the binding free energy accurately and efficiently. The conformational flexibility of a given inhibitor and its receptor can be taken into account, resorting to a wise strategy that employs a rapid and lower level method such as flexible inhibitor/rigid receptor docking at the beginning (Section 3), and turning to the more accurate and quantitative method as the MM/PBSA analysis 35 sampled by molecular dynamics (MD) simulations only once the best pose has been identified and all eventual available criteria have been satisfied.…”

“…22 The highly predictive three-dimensional pharmacophore model generated consisted of two hydrogen bond donor and one hydrophobic aromatic feature, as illustrated in Figure 2B. Using these constraints combined with the information on key amino acids identified by mutation (see Section 2), we searched for a putative binding site of our molecular series on BVDV RdRp, following our recently published successful protocol developed for studying allosteric inhibitors of BVDV, 26,31 and Polio-virus helicase.…”

“…To identify the molecular structure requirements in the available series of compounds to act as effective BVDV inhibitors, a three-dimensional pharmacophore model was also developed, 22 consisting of two hydrogen bond donor groups and one hydrophobic aromatic feature. The application of this simple but effective ligand-based approach to a test set of compounds showed that it is able to accurately predict the activity of all compounds towards the viral pathogen.…”