Use Of The R-Group Descriptor for Alignment-Free QSAR

Hirons, Linda; Holliday, John D.; Jelfs, Stephen; Willett, Peter; Gedeck, Peter

doi:10.1002/qsar.200510102

Cited by 13 publications

(7 citation statements)

References 19 publications

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“…Based on the results of molecular modeling, an interplay mechanism of BMS small-molecule ligands with PD-L1 was proposed. Finally, R-group based QSAR analysis (Holliday et al, 2003; Hirons et al, 2005) and molecular docking were constructed on the reported BMS small-molecule inhibitors. The results of this study would provide a good guidance for the discovery of novel small-molecule inhibitors and structural modification of BMS small-molecule inhibitors targeting PD-L1.…”

Section: Introductionmentioning

confidence: 99%

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Shi

Bai

et al. 2019

Front. Chem.

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Recently, small-molecule compounds have been reported to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1. All these inhibitors had a common scaffold and interacted with the cavity formed by two PD-L1 monomers. This special interactive mode provided clues for the structure-based drug design, however, also showed limitations for the discovery of small-molecule inhibitors with new scaffolds. In this study, we revealed the structure-activity relationship of the current small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. During the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to have a more stable binding mode with one PD-L1 monomer than the other and the small-molecule inducing PD-L1 dimerization was further stabilized by the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on both monomers and the water bridges involved in ALys124. The unbinding process prediction showed that the PD-L1 dimerization kept stable upon the dissociation of ligands. It's indicated that the formation and stability of the small-molecule inducing PD-L1 dimerization was the key factor for the inhibitory activities of these ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities by structural modifications. Taken together, the results in this study could guide the structural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.

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Section: Introductionmentioning

confidence: 99%

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Shi

Bai

et al. 2019

Front. Chem.

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“…It is intuitive that the set of conformers selected should be representative of the entire conformational space; however it is not currently clear as to which method to apply in generating such a set of conformers. Alignment-free descriptor vectors [23,[65][66][67] appear to be the pre-eminent choice for the conformer problem since extant 'diverse' subset selection methods can be applied readily to select conformers that are representative of the entire conformer space and will be effective both within and between individual molecules.…”

Section: Discussionmentioning

confidence: 99%

On Scaffolds and Hopping in Medicinal Chemistry

Brown

Jacoby²

2006

MRMC

139

130

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The molecular scaffold is an oft-cited concept in medicinal chemistry suggesting that the definition of what makes a scaffold is rigorous and objective. However, this is far from the case with the definition of a scaffold being highly dependent on the particular viewpoint of a given scientist. It follows, therefore, that the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. These techniques are adapted from chemoinformatics to be applied in the design of new medicinal compounds.

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“…Previously applied to the calculation of inter-substituent similarities, which might be exploited for the identification of bioisosteric groups [16], the R-group descriptor (RGD) was more recently also the subject of QSAR investigations [17]. The RGD describes the distribution of atomic properties at a distance of n bonds (n ¼ 1, 2, 3 y) away from a core that is common to a series of compounds.…”

Section: Molecular Descriptorsmentioning

confidence: 99%

Use Of The R-Group Descriptor for Alignment-Free QSAR

Cited by 13 publications

References 19 publications

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

Computational Insight Into the Small Molecule Intervening PD-L1 Dimerization and the Potential Structure-Activity Relationship

On Scaffolds and Hopping in Medicinal Chemistry

Chapter 9 Molecular Similarity: Advances in Methods, Applications and Validations in Virtual Screening and QSAR

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