An in-silico study: Investigating small molecule modulators of bio-molecular interactions

Small molecule inhibitors are commonly used to target protein targets that assist in the spread of diseases such as AIDS, cancer and deadly forms of influenza. Despite drug companies spending millions on R&D, the number of drugs that pass clinical trials is limited due to difficulties in engineering optimal non-covalent interactions. As many protein targets have the ability to rapidly evolve resistance, there is an urgent need for methods that rapidly identify effective new compounds. The thermodynamic driving force behind most biochemical reactions is known as the Gibbs free energy and it contains opposing dynamic and structural components that are known as the entropy (ΔS°) and enthalpy (ΔH°) respectively. ΔG° = ΔH° - TΔS°. Traditionally, drug design focussed on complementing the shape of an inhibitor to the binding cavity to optimise ΔG° favourability. However, this approach neglects the entropic contribution and phenomena such as Entropy-Enthalpy Compensation (EEC) often result in favourable bonding interactions not improving ΔG°, due to entropic unfavorability. Similarly, attempts to optimise inhibitor entropy can also have unpredictable results. Experimental methods such as ITC report on global thermodynamics, but have difficulties identifying the underlying molecular rationale for measured values. However, computational techniques do not suffer from the same limitations. MUP-I can promiscuously bind panels of hydrophobic ligands that possess incremental structural differences. Thus, small perturbations to the system can be studied through various in silico approaches. This work analyses the trends exhibited across these panels by examining the dynamic component via the calculation of per-unit entropies of protein, ligand and solvent. Two new methods were developed to assess the translational and rotational contributions to TΔS°, and a protocol created to study ligand internalisation. Synthesising this information with structural data obtained from spatial data on the binding cavity, intermolecular contacts and H-bond analysis allowed detailed molecular rationale for the global thermodynamic signatures to be derived.