Question

Describe three different lead discovery approaches (other than rational)!?

And how would you discover a lead by a rational approach?

Answer 1

Answer:

Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified by the process of drug discovery.

There are different approaches for lead discovery as follows

1. Traditional Library Screening

The goal of screening of a library, in whole or in part, is to discover compounds with modest activity against a target. The active compounds discovered through a screen are called hits. Targets are normally enzymes or receptors, so the term activity refers to an IC50 or EC50 value.

Compounds are normally stored as a stock solution and to be dispensed as needed by robotic equipment. Dimethylsulfoxide (DMSO) is a preferred solvent. The purity of compounds in the library is an important factor. Reaction side products should be completely removed from a compound in a library.

High-throughput screens involve some type of biochemical test for binding of the molecule of interest to a target. The screens are done in 96-, 384-, or 1,536-well microtiter plates. As a library is screened, small amounts of each member of the library will be placed in each well and tested for activity. If each library member is a single compound, a well will contain a single compound or a mixture of compounds. Regardless of whether a library consists of single compounds or mixtures, promising hits in an assay must have their activity confirmed. This process ensures that pure material of a known structure is used in the screen. The testing of pure material also ensures that the activity data is as accurate as possible. Overall, compound libraries are a vital resource in a productive drug discovery program. Molecular biological information on a target can advance a drug search only so far. Random screening of either an entire or partial library, then, hopefully provides promising hits for the lead optimization.

2. Fragment-Based Screening

Fragment libraries are not different from traditional compound libraries except molecules in a fragment library are smaller. Fragments have a molecular weight of only 120 to 250 g/mol. Limiting molecular weight dramatically decreases diversity in the library. Smaller molecules have fewer potential sites for intermolecular binding than larger molecules. Hence, small molecules rarely bind as strongly as larger compounds.

The key to discovering hits through fragment-based screening involves two steps.

a. Discovering binding fragments

b. Ensuring that, fragments must be properly connected and rescreened to discover a hit

Proper connection of the fragments would be a challenge. The tether between the fragments must be the correct length and placed appropriately. Successful examples of fragment-based hit discovery involve targets with two or more active site pockets, each of which can accommodate a fragment-sized group. Because fragment connection requires a spatial understanding of how a fragment and target interact, fragment-based screening methods need to have a three-dimensional model of the target. In x-ray crystallography, x-ray structures of fragments bound to a target provide both the site and position of binding. With quality structural information to guide the drug discovery group, determining the ideal linker length and position is a much easier task.

3. Virtual Screening

Virtual screening is also called in silico screening, is a new approach to library testing. In this approach, computerized molecular models of both the target and library member are aligned to determine potential complementary intermolecular interactions. Molecules with a high level of complementarity, indicates potentially strong binding, are flagged for synthesis and testing. A virtual screen needs sufficient knowledge about the target protein structure. Virtual screening does not require an existing compound library. Any molecule imaginable can be modeled in a computer and screened. The virtual library should consist of realistically synthesizable compounds. Selected compounds are also normally filtered for those with desired structural elements.

Once starting conformations of the target and library members have been established, each library member is virtually brought into contact with the target to determine the possibility of binding. This is called docking, follows the induced-fit model in which the interacting molecules influence each other’s conformations until a minimum energy is reached. After a compound has been docked to the target, the binding energy is estimated in a process called scoring. Standard intermolecular forces, contact forces, dipole interactions, and hydrogen bonding are approximated and totaled.

Discovering a lead by a rational approach

Rational or structure-based drug design is a common method used to identify a lead compound and move forward for further development.

This approach is applied in the discovery of novel lead drugs. Its rapid development is due to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few years. The most advantage of this approach is it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study.

The rational development of a new drug follows a three-step process.

a. Identification of target, such as a receptor or enzyme relating to a particular disease state

The understanding of the molecular mechanisms of disease has allowed the identification of many biological macromolecules implicated in disease, many of which are involved in specific cellular-signalling pathways.

b. This target then needs to be fully characterized and a molecule must be designed that binds to target

The target needs to be characterized completely using many advanced methods.

c. Designing a drug with the desired pharmacological activity that will bind specifically to a given target.

Design a molecule that has binding characteristics with target.

Summary: The rational or structure-based drug design methods have great power when the right approach is taken for the appropriate problem.

End of answer

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