Reviewing Ligand-Based Rational Drug Design: The Search for an ATP Synthase Inhibitor

Abstract

Following major advances in the field of medicinal chemistry, novel drugs can now be designed systematically, instead of relying on old trial and error approaches. Current drug design strategies can be classified as being either ligand- or structure-based depending on the design process. In this paper, by describing the search for an ATP synthase inhibitor, we review two frequently used approaches in ligand-based drug design: The pharmacophore model and the quantitative structure-activity relationship (QSAR) method. Moreover, since ATP synthase ligands are potentially useful drugs in cancer therapy, pharmacophore models were constructed to pave the way for novel inhibitor designs.

Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

“…Pharmacophore models can be used to make an ensemble of abstract steric and electronic features representing macromolecular (target protein) interactions with drug-like small molecules 115,116 . In other words, three-dimensional arrangement of these features such as hydrophobic centroids, aromatic rings and hydrogen bonds are representation of the binding mode between the ligand and the target 116,117 . Pharmacophores are generated from common features of active ligands, which are identified by aligning or superimposing the conformers of either ligand-target complexes or known active molecules 117 .…”

“…In other words, three-dimensional arrangement of these features such as hydrophobic centroids, aromatic rings and hydrogen bonds are representation of the binding mode between the ligand and the target 116,117 . Pharmacophores are generated from common features of active ligands, which are identified by aligning or superimposing the conformers of either ligand-target complexes or known active molecules 117 . Multiple degenerate atomic models can potentially be output from pharmacophore modeling programs requiring further optimization and validation to select the best one.…”

“…Multiple degenerate atomic models can potentially be output from pharmacophore modeling programs requiring further optimization and validation to select the best one. Pharmacophore models are commonly used for virtual screening of active small molecules from large compound database [115][116][117] . Such approaches can be more efficient than docking for certain targets, especially when a large number of existing known active compounds are available 118 .…”

Introduction to Cancer Systems Biology

“…5 Docking simulation such as protein-drug or DNA-drug docking has the potential to enhance drug development. 6 These methods can be beneficial for disease biomarker and target identification as well as drug discovery. …”

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“…Virtual screening (VS) is the process of evaluating a library of compounds using a computational model in order to rank, and thus screen for molecules that exhibit desired characteristics, LBVS (Ligand based virtual screening) was adopted in this study and pharmacophore model generated from a set of known ligands which was used in the virtual screening to elicit specific inhibitors against accD3 protein 40,41 .…”