The Use of Dynamic Pharmacophore in Computer-Aided Hit Discovery: A Case Study

Abstract

In recent years pharmacophore modeling has become increasingly popular due to the development of software solutions and improvement in algorithms that allowed researchers to focus on interactions between protein and ligands instead of technical details of the software. At the same time, progress in computer hardware made molecular dynamics (MD) simulations on regular PC hardware possible. MD simulations are usually used, within the virtual screening process, to take into account the flexibility of the target and studying it in more realistic way. In order to do so, it is customary to use simulations before the virtual screening process and then use them for collecting some specific conformation of the target used. Furthermore, some researchers have demonstrated that the use of multiple crystal structures of the same protein can be valuable to better explore the role of the ligand within the binding pocket and then evaluate the most important interactions that are created during the host-guest recognition process. Findings derived from the MD analysis, especially focused on interactions, can be in fact exploited as features for pharmacophore generation or constraints to be used in the molecular docking as integrated steps of the whole virtual screening process. In this chapter, we will present the recent advances in the field pharmacophore modeling combined with the use of MD, a field well explored by our research group in the last 2 years.

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

“…From the structural analysis of the two compounds compared, the common residues of the protein complex interacting with PB and E7107 were: V1078, V1110, V1114 and L1066 of the subunit SF3B1 and R38 and Y36 in the PHF5A subunit [ 57 ] . Starting from the two crystal structures, a pharmacophore map was created using LigandScout v.4.4 [ 46 , 47 ] , and geometrically common features were selected, thus removing two distal features. As a result, six common pharmacophoric features were found and the common pharmacophore was created [ Figure 1 ].…”

“…LigandScout [ 46 , 47 ] software was employed to create the pharmacophore model and find the common feature between the two PDB structures by using the common pharmacophore map for virtual screening. The pharmacophore model was created, using the PDB coordinate of the ligand-protein complex (PDB IDs: 5ZYA and 6EN4).…”