Figure 1.

High-throughput supervised molecular dynamics (HT-SuMD), an automated protocol exploiting molecular simulation to perform fragment screening. The SuMD methodology is summarized with a specific focus on the tabu-like algorithm controlling acceptance or rejection of short unbiased MD simulations, depending on how the distance between the fragment under investigation and the binding site center of mass (d_cmⁿ) changes during the trajectory. A density-based clustering algorithm (DBSCAN) clustering algorithm is used to perform a geometrical discretization of SuMD trajectories and identify relevant fragment conformations. Each cluster is then characterized based on four geometric and energetic indicators: (i) cluster size; (ii) hydrogen bond presence; (iii) hydrophobic contribution of binding; and (iv) protein–ligand MMGBSA binding interaction energy. Once all clusters have been characterized, a consensus scoring filter is applied to identify hit fragment molecules.