Lead compounds drug-likeness

Lipinski, C. A. (2004) Lead- and drug-like compounds the rule-of-five revolution. Drug Discov. Today Technologies, 1, 337-241. 

Marrero-Ponce, Y, Huesca-Guillen, A. and Ibarra-Velarde, E. (2005) Quadratic indices of the molecular pseudograph s atom adjacency matrix and their stochastic forms a novel approach for virtual screening and in silica discovery of new lead paramphistomicide drugs-like compounds. J. Mol. Struct. (Theochem), 717, 67-79. 

Fig. 2 Hapten/peptide and p-i concept of T cell stimulations by drugs, (a) Haptens haptens are chemically reactive compounds. Drugs like penicillin are haptens they bind to lysine amino acids in proteins or by the SH-group formed by opening the thiazolidine ring. This covalent binding can modify soluble or cell bound molecules. They can even bind directly to the immunogenic major histocompatibiliy complex (MHC)/peptide complex on antigen presenting cells (ARC), either to the embedded peptide or to the MHC molecule itself. Thus, the chemical reactivity of haptens can lead to...

Molecular structure has been shown to influence absorption. By examining the structural characteristics of drugs that were in use, certain common characteristics of well-absorbed molecules were identified, commonly referred to as the rule of five. Some investigators have used this as a basis for characterizing the drug-likeness of a lead chemical. Other factors also come into play including receptor activity, metabolism profile and for CNS-active compounds, an ability to cross the blood-brain barrier. 

Lead-likeness and drug-likeness were introduced to describe high-quality medicinally relevant compounds and a great deal of effort was devoted over the last 10... 

In summary, such simple classification schemes for drug-likeness can, in a very fast and robust manner, help to enrich compound selections with drug-like molecules. These filters are very general and cannot be interpreted any further. Thus, they are seen rather as a complement to the more in-depth profiling of leads and drugs by using molecular properties and identifying trends in compound series. 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

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