A medicinal chemistry perspective on melting point: matched molecular pair analysis of the effects of simple descriptors on the melting point of drug-like compounds

The influence of simple molecular descriptors on the melting point temperature (Tm) has been investigated using a matched molecular pair (MMP) analysis. This method has been used to identify small structural differences between pairs of molecules, which are related to changes in Tm. Our analysis shows that the number of hydrogen bond donors, hydrogen bond acceptors and rotatable bonds has a significant effect on the Tm of a molecule. Hydrogen bond donors have the most pronounced effect. Furthermore, the studies reveal that not ClogP but rather the number of bromine and iodine atoms has a marked effect on the Tm. The results of our MMP analysis are discussed within the context of drug solubility optimization.