Probing interaction requirements in PTP1B inhibitors: a comparative molecular dynamics study.

Molecular dynamics studies were performed on eight different crystal structure complexes of protein tyrosine phosphatase 1B (PTP1B) to study energy components and interactions important for the binding of substrates/inhibitors. Calculation of the binding free energy and the different components was accomplished using molecular mechanics--Poisson-Boltzmann surface area and--generalized Born surface area methods. Free energy was decomposed into individual amino acid contribution to know the relative importance. Hydrogen-bond existence maps for individual ligands were monitored comprehensively. It is evident from flexibility studies that the complexes exhibit rigidity in WPD loop, which is the first prerequisite for PTP1B inhibition. The study suggests that for designing active site inhibitors, there should be an optimum balance between total electrostatic and van der Waals interactions. It is also established that for allosteric inhibitors, van der Waals interactions are significant in addition to electrostatic interactions that are responsible for strong binding affinity.