Novel approach to structure-based pharmacophore search using computational geometry and shape matching techniques.
Computationally efficient structure-based virtual screening methods have recently been reported that seek to find effective means to utilize experimental structure information without employing detailed molecular docking calculations. These tools can be coupled with efficient experimental screening technologies to improve the probability of identifying hits and leads for drug discovery research. Commercial software ROCS (rapid overlay of chemical structures) from Open Eye Scientific is such an example, which is a shape-based virtual screening method using the 3D structure of a ligand, typically from a bound X-ray costructure, as the query. We report here the development of a new structure-based pharmacophore search method (called Shape4) for virtual screening. This method adopts a variant of the ROCS shape technology and expands its use to work with an empty crystal structure. It employs a rigorous computational geometry method and a deterministic geometric casting algorithm to derive the negative image (i.e., pseudoligand) of a target binding site. Once the negative image (or pseudoligand) is generated, an efficient shape comparison algorithm in the commercial OE SHAPE Toolkit is adopted to compare and match small organic molecules with the shape of the pseudoligand. We report the detailed computational protocol and its computational validation using known biologically active compounds extracted from the WOMBAT database. Models derived for five selected targets were used to perform the virtual screening experiments to obtain the enrichment data for various virtual screening methods. It was found that our approach afforded similar or better enrichment ratios than other related methods, often with better diversity among the top ranking computational hits.
Ebalunode
Jerry Osagie
JO
Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central University, 1801 Fayetteville Street, Durham, North Carolina 27707, USA.
Ouyang
Zheng
Z
Liang
Jie
J
Zheng
Weifan
W
D002626:Chemistry, Pharmaceutical; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000737:chemistry; D013937:Thymidine Kinase / Q000737:chemistry; D014961:X-Ray Diffraction
D011960:Receptors, Estrogen; D013937:Thymidine Kinase; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016333:HIV Protease