Docking Screens for Novel Ligands Conferring New Biology

Abstract

It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably rank order high-scoring molecules), it can often can distinguish likely from unlikely ligands, often with hit rates above 10%. Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible. Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them. Like any technique, controls are crucial, and key experimental ones are reviewed. With such controls, docking campaigns can find ligands with new chemotypes, often revealing the new biology that may be docking’s greatest impact over the next few years.

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

“…[62][63][64] In this case, energy minimization of the system is required, but in our experience, many force elds neglect the conformational preferences based on weak intramolecular interactions and oen lead to unrealistic ligand geometries.…”

“…[62][63][64] However, in our experience, many force elds neglect weak intramolecular interactions and conformational preferences of the ligand, 66 oen leading to unrealistic predicted geometries of the ligand in the binding site. Bearing this information in mind, this research should raise the awareness of researchers and potentially impact the docking algorithms, which tend to assume that the sulfonyl group is a strong hydrogen bond acceptor.…”

Structure-Based Discovery of Small Molecules Binding to RNA

“…The main difference between the different conformational search algorithms is how the degrees of freedom of the ligand are treated while the scoring functions differ based on which underlying theory they are built on. Docking is routinely used for ligand discovery for protein targets [28] and there are several comprehensive textbooks and review articles about docking in general (e.g., [26,29,30]). Therefore, we will only give a concise overview and focus instead on what is specific for RNA-ligand docking compared to the more established protein-ligand docking.…”

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…These limitations stem, mostly, from the inability of the scoring functions in molecular docking algorithms to account for local and global macromolecular dynamics, in addition to inability to accurately predict covalent interactions and solvent accessibilities: (1) in most cases the protein is modeled as a rigid structure without flexibility; (2) solvation of the active/binding site and of the ligand is usually excluded; (3) free-energy estimation of protein-ligand complexes is largely ignored [357,361,362]. Molecular docking methodology, cavity definition and search algorithms, and thermodynamic scoring functions continue to improve, however [363].…”