By Dr. Ahmad Sheikh, AbbVie   While new chemical entities represent majority of the drugs approved in the last five years, the diversity and complexity of these molecules continue to increase and cover chemically labile structures such as pro-drugs, large, small molecules specifically designed to disrupt protein-protein interactions, and heterobifunctional molecules called PROTACs. These complex molecules are better suited for modulation of large, flat, and groove-shaped binding sites representing half of druggable targets. The structural complexity and diversity make overall pharmaceutical development challenging and developability indicating properties need to be assessed early in the Medical Chemistry Design Cycle with sufficient accuracy. Assessment of thermodynamic crystalline solubility in lead optimization is one such property. Our physics-based ensemble approach which uses predicted crystal structures and modified FEP protocols results in very close match (< 1 log unit) to experimental data for structurally related molecules. We demonstrate the importance of such predictions by observing upto 4 log unit differentiation not captured by HT solubility screening assays or classic amorphous solubility FEP+ predictions. Similarly, molecular conformations in polar (aqueous) and non-polar (membrane) media and calculation of their Boltzmann Weighted 3D-Polar Surface Area can provide information on shielding of polarity, which can be used to design molecules with improved passive permeability. When molecular complexity becomes unavoidable as in the case of disease eliminating direct activity antivirals for Hepatitis C, a robust and toolkit of advanced computational and experimental approaches is key to make a difference in patient’s lives.