Drug Likeness

Because of the charge distribution, pJ A predictions of mesomeric and heterocyclic structures are especially difficult and often incorrect. Unfortunately, most drug-like molecules contain these structural elements. 

Current computer programs use huge databases of experimental data to obtain more reliable results. 

Combinatorial libraries are one of the starting points of the drug development process that comprises a number of phases and lasts many years in total. 

After synthesis, the compounds are screened in vitro against biological targets. This results in a certain number of so-called hits for each target. Lead structures are selected from the hits and optimized to only a few drug candidates. These will go into the clinical phases of drug development. In every phase of this process a compound or lead structure can drop out for a variety of reasons. 

Because of the very high cost of the entire process, it is desirable to identify compounds that will fail to become a drug as early as possible. Analyses of candidates cancelled in clinical studies show that many of them do not even pass the very basic filters. Millions of dollars can be saved if these molecules are eliminated earlier. At best, the non-drug-hke compounds are already removed from the virtual library before the start of synthesis [35]. 

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Prediction of various physicochemical properties such as solubihty, lipophhicity log P, pfQ, number of H-donor and acceptor atoms, number of rotatable bonds, polar surface area), drug-likeness, lead-likeness, and pharmacokinetic properties (ADMET profile). These properties can be applied as a filter in the prescreening step in virtual screening. 

Other filters used for prefiltering account for lead- [22, 23] or drug-likeness [24-26], an appropriate ADMET profile [27-30], or favorable properties concerning receptor binding [31, 32]. 

Most practical implementations of drug-likeness use a computational model which takes as input the molecular structure, together with various properties, and predicts whether the molecule is drug-like or not. Some of these models may be very simple, such as a series of substructural filters. Only those molecules which pass all of these filters are output, Such filters can be used to eliminate molecules that contain inappropriate functionality. 

W P Walters and M A Murcko 1998. Can We Learn to Distinguish Between Drug-like and indrug-like Molecules Journal of Medicinal Chemistry 41 3314-3324. 

Where do new drugs like this come from ... 

Many drug-like molecules have aromatic substituents and thus have limited aqueous solubility. A routine practice is to dissolve stock drugs in a solvent known to dissolve many types of molecular structures. One such solvent is... 

In general, there are three milestones for the drug discovery process. The first is the identification of a verified hit series (primary activity in a related series of molecules), the second the determination of a lead series (series with primary activity and drug-like properties), and the third a clinical candidate (activity, positive pharmaceutical, and pharmacokinetic properties devoid of toxicity). An example... 

There is evidence to suggest that drug-like structures exist in clusters in chemical space (privileged structures). Identification of these can greatly enhance success in screening. 

Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Tox. Meth. 44 235-249. 

Proudfoot, J. R. (2002). Drugs, leads, and drug-likeness An analysis of some recently launched drugs. Bioorgan. Med. Chem. Lett. 12 1647-1650. 

Class IB drugs like lidocaine, phenytoin or mex-iletine preferentially bind to the inactivated state. Lidocaine, a local anaesthetic, can be used intravenously for antiarrhythmic treatment. It is one of the classical dtugs used in emergency medicine for the... 

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

Low affinity use-dependent NMDA recqrtor antagonists meet the criteria for safe administration into patients. Drugs like amantadine and memantine have modest effects on Parkinson s disease and are used as initial therapy or as adjunct to l-DOPA. Their adverse effects include dizziness, lethargy and sleep disturbance. 

Katp channels are the targets for two classes of therapeutic agents, hypoglycaemic drugs like glibencla-mide or nateglinide and potassium channel openers like... 

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

Walters WP, Murcko MA (2002) Prediction of drug-likeness. Adv Drug Deliv Rev 54(3) 25 5-271... 

Cytochrome P450 2C9 Low activity in about 10% (heterozygotes) and very low activity in about 0.8% (homozygotes) of Caucasian populations. Prolonged action of several CYP2C9 inactivated drugs like phenytoin, tolbutamide, ibuprofen, or S-warfarin. 

Cytochrome P450 2C19 Deficient activity in about 3% of Caucasian populations and in about 20% of Asian populations. Prolonged action of several CYP2C19 inactivated drugs like omeprazole or diazepam in the poor metabolizers. 

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