Identification of a Lead Compound

Endogenous sources (drug candidates from molecules within us e.g., insulin for diabetes) 

Exogenous sources ethnobotany (drug candidates from natural product sources) 

Elegant though some of these may sound, serendipity has historically been the most successful discoverer of drugs. 

1 Lead Compound Identification— A Short History of Drug Discovery 

Since the dawn of humankind, efforts have been made to discover remedies for the ailments of life. Although there are numerous examples of the trials and tribulations associated with these efforts, the story of epilepsy affords many instructive anecdotes. 

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Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

Empirical drug discovery, despite its successes, is not without intrinsic problems the identification of a lead compound is divorced from an understanding of its mechanism of action, making lead optimization difficult since there is no easily quantifiable way to ascertain whether an analog will have greater effect. Additionally, the value of an empirical screen depends on its predictive ability. In some cases, such as acid hyposecretion or H2-receptor binding assays. 

This approach is based on the chiral dihydronaphthalene motif, represented by compound (f )-8. Generally, this motif is found in a number of biologically active molecules and therefore it is a chemically privileged structure in the sense of being a starting point for the identification of a lead compound for evaluation [30]. 

The discovery of new drugs is a long and complex process. It starts with the identification of a lead compound which elicits a desirable effect. Traditionally, lead compounds have been selected by screening large corporate databases or natural products for biological activity. These compounds are then modified to improve their potency, specificity, and in vivo activity. 

Design or identification of a lead (prototype) compound (section 3.2)... 

A qualitative process approach to accelerated development emphasizes the elimination of drug candidates from the pipeline. This approach targets the advanced evaluation of specific pharmaceutical properties. The reward is not necessarily intuitive introduce a qualitative process change earlier in the drug development pipeline, resulting in the proactive identification of promising lead compounds and the utilization of fewer resources during the costly clinical development phases. This approach is driven by kinetic ... 

Further analysis of the UV spectrum revealed that this compound is a gallic acid derivative. A search of the Dictionary of Natural Products for molecular ion and plant genus name leads to the identification of a known compound - Pterocaryanin B. The compounds with poly-hydroxyl groups in their structures are very well known as tyrosinase inhibitors and are responsible for the inhibition of melanin synthesis. Therefore, no further isolation was necessary. 

In addition to extending the utility of analytical NMR, these developments have had a direct impact on screening methodologies, where NMR spectroscopy may now be used directly as a rapid and sensitive method for the characterization of binding affinities of mixtures of compounds in combinatorial libraries.3,9 11 A powerful screening method based on observation of NMR signals from a protein target has been developed by researchers at Abbott laboratories.12 Termed SAR (structure-activity relationship) by NMR, this technique has proved to be extremely valuable for the identification of novel lead compounds. 

Whole cell growth inhibition screens combined with subsequent target identification using molecular methods have proven viable approaches to the discovery of novel antibacterial inhibitors. Andries and colleagues (2005) at Johnson Johnson employed whole cell assays to discover a series of antimycobacterial diarylquinolines (DARQs). Chemical optimization of a lead compound led to DARQ derivatives exhibiting potent in vitro activities against several mycobacteria including Mycobacterium tuberculosis (Andries et al., 2005 Ji et al., 2006), with MICs below 0.5 pg/mL. Antimycobacterial efficacy in vivo was confirmed for three of the derivatives. 

Besides the usefulness of infrared spectra in the identification of individual bonds, the technique is of great value in leading to an absolute identification of a pure compound. Because of the large numbers of vibrational modes in a molecule, the complete infrared spectrum of a given molecule will be very complicated and quite... 

Although interaction effects may lead to uncertainties in the idem iheation of functional groups contained in a compound, it is this very effect that provides the unique features of an IR absorption spectrum thal are so important for the positive identification of a specific compound. 

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