Optimization of leads

Lead identification/optimization is the one of the most important steps in drug development. The chemical structure of the lead compound is used as a starting point for chemical modifications in order to improve potency, selectivity. Potency, efficacy and selectivity are not the only needed characteristics of a drug; the drug has to have certain pharmacokinetic parameters so as to be involved in further drug development Once a molecule is identified, the next step is to check its ADMET (Adsorption, Distribution, Metabolism, Excretion and Toxicity) properties. If the molecule has no toxicity and no mutagenicity either, it has potential for use as lead molecule. Further optimization gives better quality of lead molecules. These may subsequently be developed as drug(s)

New compounds that show promising therapeutics potential based on the biological activity are subject to further studies aimed at developing a promising pharmaceutical candidate for preclinical studies and clinical trials.

Optimization of leads basically involves the following goals

• Suitably altering the lead so as to improve the ADME characteristics of the drug
• improving pharmacokinetic characterization of Drugs

Optimization of a lead is also expected to remedy the following shortcomings by molecular manipulation which includes

• Freedom from mutagenicity

• Freedom from teratogenicity

• Chemical stability

• Synthetic or biological accessibility

• Acceptable cost

• Ability to patent

• Clinical efficacy

• Solubility

• Satisfactory taste

• Ability to formulate satisfactorily for administration

• Freedom from an idiosyncratic problem.

 

The Nobel prize in chemistry for the year 2013 was awarded jointly to Martin Karplus (Harvard University) , Michael Levitt (Stanford School of Medicine) and Arieh Warshel (University of Southern California) for “the development of multi-scale models for complex chemical systems”.

The fact that scientists these days can use computers to carry out experiments has yielded a much deeper understanding of how chemical processes play out. Computer models mirroring real life have become crucial for most advances made in chemistry today. Chemists earlier used to create models of molecules using plastic balls and sticks. Today, the modelling is carried out in computers.

Wayback in the 1970s, Martin Karplus, Michael Levitt and Arieh Warshel laid the foundation for the powerful programs that are used to understand and predict chemical processes.

The strength of the methods the trio have developed is that they are universal. They can be used to study all kinds of chemistry –  from the basic molecules of life to the complex industrial chemical processes enabling scientists to optimize solar cells, catalysts in motor vehicles and even drugs, to name a few.

Their methods have been devised basing on both classical and quantum physics. For example, in simulations of how a drug couples (DRUG interaction) to its target protein in the body, the software performs quantum theoretical calculations on those atoms in the target protein that are interacting with the drug. The remainder of the large protein is simulated using less demanding classical physics . In the present day computer has become a tool as important the test tube for a chemist. The Simulations are so perfect that they mimick the outcome of traditional experiments.

The Royal Swedish Academy of Sciences (RSAS) said “It is a tantalizing thought. The computer models that have been developed by the three Nobel laureates are powerful tools. Exactly how far they can advance our knowledge is for the future to decide”.