Partition coefficient drug design

Abraham, M.H., Chadha, H.S. and Mitchell, R.C. (1995). Hydrogen Bonding. Part 36. Determination of Blood Brain Distribution Using Octanol-Water Partition Coefficients. Drug Design Discovery, 13,123-131. 

Although experimental partition coefficients are the values of reference, drug design often necessitates log evaluations before the compound has been synthesized. Consequently, various methods have been developed to predict lipophilicity [188], and they generally apply only to neutral compounds in the water-OCT system. 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

Absorption, in general, is treated as a physicochemical transport process based on computations of logP (the octanol/water partition coefficient) and solubility governed by factors such as polar surface area on the molecule. It is conceivable that SNPs in drug transporter genes will affect the pharmacokinetic properties of compounds and, therefore, these may have to be taken into consideration in the design process. 

A quantitative analysis of the structure-retention relationship can be derived by using the relative solubility of solutes in water. One parameter is the partition coefficient, log P, of the analyte measured as the octanol-water partition distribution. In early work, reversed-phase liquid chromatography was used to measure log P values for drug design. Log P values were later used to predict the retention times in reversed-phase liquid chromatography.The calculation of the molecular properties can be performed with the aid of computational chemical calculations. In this chapter, examples of these quantitative structure-retention relationships are described. 

Viswanadhan, V. N., et al., An Estimation of the Atomic Contribution to Octanol-Water Partition Coefficient and Molar Refractivity from Fundamental Atomic and Structural Properties Its Uses in Computer Aided Drug Design. Math. Comput. Model., 1990 14, 505-510. 

Hopfinger, A. J., and R. D. Battershell, Application of SCAP to Drug Design 1. Prediction of Octanol-Water Partition Coefficients Using Solvent-Dependent Conformational Analyses. J. Med. Chem., 1976 19, 569-573. 

The thickness of the tissue, partition coefficient, and the diffusion coefficient are properties of the mucosa and cannot be altered. Designing appropriate formulations that heed the necessary conditions can vary the surface area for delivery of the drug, time of contact, and the free drug concentration. The partitioning of the drug into the membrane will depend on... 

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