Abstract
Pharmacophore-based virtual screening is an important and leading compound discovery method. However, current pharmacophore generation algorithms suffer from difficulties, such as ligand-dependent computation and massive extractive chemical features. On the basis of the features extracted by the five probes in Pocket v.3, this paper presents an improved receptor-based pharmacophore generation algorithm guided by atomic chemical characteristics and hybridization types. The algorithm works under the constraint of receptor atom hybridization types and space distance. Four chemical characteristics (H-A, H-D, and positive and negative charges) were extracted using the hybridization type of receptor atoms, and the feature point sets were merged with 3 Å space constraints. Furthermore, on the basis of the original extraction of hydrophobic characteristics, extraction of aromatic ring chemical characteristics was achieved by counting the number of aromatics, searching for residual base aromatic ring, and determining the direction of aromatic rings. Accordingly, extraction of six kinds of chemical characteristics of the pharmacophore was achieved. In view of the pharmacophore characteristics, our algorithm was compared with the existing LigandScout algorithm. The results demonstrate that the pharmacophore possessing six chemical characteristics can be characterized using our algorithm, which features fewer pharmacophore characteristics and is ligand independent. The computation of many instances from the directory of useful decoy dataset show that the active molecules and decoy molecules can be effectively differentiated through the presented method in this paper.
Highlights
The concept of pharmacophore was firstly introduced by Ehrlich in 1909(Ehrlich, 1909)
Compared with the early work on Pocket v.2 and v.3, we propose a novel solution that aims at filtering out feature points with less pharmaceutical effect by adding aromatic features and SP hybridization form
A series of experiments was conducted to validate the effectiveness of the presented pharmacophore extraction method
Summary
The concept of pharmacophore was firstly introduced by Ehrlich in 1909(Ehrlich, 1909). Structure-based virtual screening of pharmacophore has been developed as an important method for computeraided drug design (Güner, 2002; Chen, 2013; Wang et al, 2017) In this case, the protein may contain ligand (holo structure) or not (apo structure). With the rapid progress of X-ray crystallography and nuclear magnetic resonance technologies in the determination of the protein structure of drug targets (Lam et al, 1994; Erickson et al, 2004), the pharmacophore constructed using apo protein structures becomes feasible. This method of producing a pharmacophore model directly from protein crystal structures can reveal the key elements of the receptor-ligand binding model (Böhm, 1992a)
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