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Background
This project aims to explore how accurate it is to use available software to predict the solubility of small organic (drug-like) molecules using available software.
To do this we will calculate solubility values for molecules where the solubility has been measured experimentally. We will place the conclusions in the context of what is already known in the literature about this measured:experimental correlation.
Drug-like molecules can be defined as molecules or compounds exhibiting specific characteristics and properties which are crucial to the development of potential pharmaceutical drugs. These properties determine the pharmacokinetics of the drug, where favorable absorption, distribution, metabolism, and elimination (ADME) properties are required. Among these properties, aqueous solubility and hydrophobicity have a profound impact on the drug-like properties of a molecule as they determine a drug's bioavailability or its ability to dissolve in physiological fluids and achieve its desired concentration in the systemic circulation for pharmacological response. The solubility of a drug-like molecule depends on its lipophilicity and the number of hydrogen bonds that can be formed with the solvent. The golden rule of solubility states that like dissolves like, i.e. polar materials will dissolve in polar solvents while non-polar materials tend to dissolve in non-polar solvents. Hydrophilic drugs dissolve readily in water and hence they are more soluble in physiological fluids whereas hydrophobic drugs repel water and tend to form aggregation.
The Lipinski's rule of 5 formulated by Christopher Lipinski and colleagues in 1997, is valuable in determining the drug-likeness of a molecule for oral administration. According to this rule, poor absorption and permeation occurs when there are more than 5 hydrogen bond donors and 10 hydrogen bond acceptors, the molecular weight is greather than 500 Daltons, and the calculated log P is greater than 5. Compounds that fall into one or more of these categories may have difficulty crossing the cell membranes, thereby having lower bioavailability and effectiveness as orally active drugs.
Log P is defined as the logarithm of the partition coefficient of unionized compound between organic solvent, typically octanol, and water. It is a measure of the hydrophobicity of a compound by assessing the distribution of a molecule between hydrophobic and hydrophilic environments. Compounds with a positive log P value are hydrophobic and tend to partition into non-polar environments whereas compounds with a negative log P value are hydrophilic and has a higher affinity for aqueous phase.
Kinetic solubility refers to the rate at which the solute dissolves, typically in the early stages of dissolution. In most cases, the kinetic solubility of a compound is determined using a stock solution dissolved in an organic solvent, typically dimethyl sulfoxide (DMSO). It may be affected by factors such as stirring rate, temperature and particle size.
In thermodynamic solubility, also known as equilibrium solubility, the dissolved compound is in equilibrium with the undissolved material in excess, and this usually happens at the end of the dissolution process. It can be influenced by factors such as temperature, pressure and the energy changes associated with the dissolution process.
There are also studies exploring the relationship between drug solid state properties and solubility：here and here