Insight into Rational Drug Design

By Sarah MooreReviewed by Emily Henderson, B.Sc.

Rational drug design overcomes the limitations of traditional screening processes

The traditional drug design programs that were the sole route to drug discovery prior to the 1960s relied on lengthy processes of screening thousands of natural and synthetic compounds to test for activity. Compounds that were identified by the time-consuming screening process would then be developed by medicinal chemists who would synthesize hundreds of similar compounds in an attempt to develop a molecule that was safe and effective for use as a drug in humans.

This approach to drug design had some major drawbacks. The costs involved were very high due to the time-consuming nature of the process. Additionally, these costs began to increase as the years went on, with the development of a single drug costing between $200 and $500 million on average. This traditional approach is also highly inefficient. While hundreds of thousands of compounds are screened and tested each year, only around 25 new drugs are introduced annually in the US, or 40-25 globally.

Further to this, the traditional approach to drug design does not identify why a compound is inactive or active, and, therefore, provides no indication as to how it may be improved on. Additionally, it gives no information as to whether the compound is specifically active toward a target protein, there is no indication as to whether the compound may activate other, unintended pathways, and cause major side effects. The traditional process of drug screening is blind and means that around 20,000 compounds must be screened to find just one drug that enters the market.

Scientists have long worked on developing an alternative process that overcomes the significant limitations of the traditional screening process. Out of these efforts emerged rational drug design, a process where drug molecules are designed specifically to bind to a target (e.g. a protein or nucleic acid) and induce a biological response with therapeutic value.

Decades of biological research have resulted in the rapid expansion of our knowledge of biological systems. In the last 50 years, our understanding of how biologically active compounds influence  target or receptor biomolecules to induce a biological response has vastly grown. This knowledge has helped to support the development of rational drug design.

The general process of rational drug design is as follows: scientists must first identify a target for a certain therapeutic need. Next, the structure of the target protein must be defined. Lastly, the drug’s structure must be designed so that it specifically interacts with the target protein. If a biological target cannot be identified, an alternative route is taken. Here, we will discuss all three major rational drug design approaches, including structure-based (as briefly described above), pharmacophore-based (an alternative approach used when the biologic target cannot be defined), and new lead generation.

Image Credit: Gorodenkoff/Shutterstock.com

Structure-based approaches

The first port of call in rational drug design is establishing the 3-dimensional structure of the known target (often a protein or a nucleic acid). The process of identifying this structure usually involves producing a working computational model from crystallographic data.

However, in recent years, the use of active ligands to develop models of the active binding site are becoming more commonly used. From this, scientists work on designing a drug that has the correct structure required to specifically bind to the target site and induce the biological activity required for therapeutic effect.

Pharmacophore-Based Approaches

In cases where scientists cannot identify a target, or they cannot determine the structure of a target, an alternative strategy is used. This approach leverages data on drugs that produce the same intended effect as the one that is being developed. Generally, it is assumed that drugs that induce the same biological activity are acting on the same pathways and likely the same biological target.

Therefore, it is also assumed that to trigger these same biological responses, the new drug must have the same set of structural features to allow it to successfully interact with the target. This method, based on the use of analogs to develop a model of the requirements to induce therapeutic activity is known as the pharmacophore model.

In the pharmacophore model, scientists first determine the three-dimensional features that are critical for biological activity. Next, the optimal combinations for the structural features are calculated. Finally, scientists design a drug structure that encompasses this optimal combination of features.

Pharmacophore approaches have benefited in recent years from advances in the fields of molecular biology, protein crystallography, and computational chemistry, which have helped to aid the accuracy of drug design binding affinity predictions.

New lead generation

Finally, de novo design methods can also be used to design new drug structures using databases of known compounds with particular structural features. Drugs designed by this approach may be created by sequentially adding or joining molecular fragments to a structure or by adding functionality by evolving the structure of a molecular scaffold.

Further Reading

• All Drug Discovery and Manufacturing Content
• Drug Discovery, Manufacturing, and Development
• What are Peptide Decoys?
• Using Artificial Intelligence to Discover New Antibiotics
• Applications of 3D printing in Drug Delivery