Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2021-12, Vol.14 (12), p.1307
• Main Authors: Cichero, Elena, Calautti, Alessio, Francesconi, Valeria, Tonelli, Michele, Schenone, Silvia, Fossa, Paola
• Format: Article
• Language: English
• Subjects: benzimidazole-based derivatives; Clinical trials; docking studies; Drug resistance; Infections; Libraries; molecular dynamic simulation; Pharmaceutical industry; Pharmacokinetics; Proteins; Respiratory syncytial virus; respiratory syncytial virus (RSV); RSV fusion inhibitors
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph14121307

Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents.