6533b7d1fe1ef96bd125c3b4
RESEARCH PRODUCT
Comparison of virtual high-throughput screening methods for the identification of phosphodiesterase-5 inhibitors.
Olli T. PentikäinenSanna NiinivehmasJukka V. LehtonenPekka A. PostilaSalla I. Virtanensubject
Cyclic Nucleotide Phosphodiesterases Type 5Virtual screeningHigh-Throughput Screening MethodsDrug discoveryChemistryGeneral Chemical EngineeringHigh-throughput screeningMedical screeningStatic ElectricityDrug Evaluation PreclinicalNanotechnologyGeneral ChemistryComputational biologyLibrary and Information SciencesMolecular Dynamics SimulationPhosphodiesterase 5 InhibitorsLigandsComputer Science ApplicationsHigh-Throughput Screening AssaysSubstrate SpecificityUser-Computer InterfaceDocking (molecular)Catalytic Domaindescription
Reliable and effective virtual high-throughput screening (vHTS) methods are desperately needed to minimize the expenses involved in drug discovery projects. Here, we present an improvement to the negative image-based (NIB) screening: the shape, the electrostatics, and the solvation state of the target protein’s ligand-binding site are included into the vHTS. Additionally, the initial vHTS results are postprocessed with molecular mechanics/generalized Born surface area (MMGBSA) calculations to estimate the favorability of ligand-protein interactions. The results show that docking produces very good early enrichment for phosphodiesterase-5 (PDE-5); however, in general, the NIB and the ligand-based screening performed better with or without the added electrostatics. Furthermore, the postprocessing of the NIB screening results using MMGBSA calculations improved the early enrichment for the PDE-5 considerably, thus, making hit discovery affordable.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-06-01 | Journal of chemical information and modeling |