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.
Highlights
New drugs were found only by a trial and error approach
The most important breakthrough came with the emergence of genomics, proteomics and the development of bioinformatics and chemoinformatics
A pharmacophore model should always be validated by ligands that are not included in the training set despite whether previously known binding mechanisms exist or not
Summary
New drugs were found only by a trial and error approach. Potentially, anything deemed to be of medicinal value in a specific disease could be tested on patients to determine its efficacy [1]. If reliable information on the 3-D structure and active sites of the target protein can be obtained from X-ray crystallography, nuclear magnetic resonance, or 3-D structure databases, and incorporated into a computer model, compounds binding to the target can be designed [8] This approach is known as “structure-based drug design”. Usually in which data pertaining to the 3-D structure of a target protein are not available, drug design can instead be based on processes using the known ligands of a target protein as the starting point. Quantitative structure-activity relationships (QSAR) and pharmacophore models are frequently used methods in the ligand-based drug design process [13]. Pharmacophore models of the ATP synthase beta subunit-binding ligands selected from existing literature are discussed here as an illustration
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