Exploration of novel molecular inhibitors for Monkeypox virus with a fragment-based drug design approach

In August 2024, the world health organization declared Monkeypox virus (MPXV) a public health emergency of international interest due to a significant increase in reported cases and the number of deaths. The MPXV is a transmissible disease spreading from animals to people via scratches, bites, or as food, then people spread it to other people by close contact including sexual activities, massages, kissing, day-to-day household contact, and caring for people with MPXV. This work aims to find novel MPXV receptor inhibitors with an application of fragment-based drug design strategy. A screening of >269,000 fragments from various online data bases has been conducted to determine their affinity for binding MPXV. Employing the 2022 version of Schrödinger software, a total number of 1600 fragments with the highest docking scores have been submitted to a fragment linking to generate 100 new molecules. The MPXV binding affinity and ADMET features of the top10 docking score ligands were then examined in more comprehensive detail. Lastly, the appropriate ligands were chosen for a molecular dynamics study in order to evaluate the stability of the ligand-receptor complex in the best three molecules. The discovered ligands might be investigated further in the field of Monkeypox inhibitor drug development.