The study of protein-protein interactions (PPIs), notably those involved in mechanisms of disease can be exploited in design of effective therapeutics. Type-2 diabetes can induce a dysfunctional endothelial cell phenotype which is also intrinsically linked to the progression of atherosclerosis and further cardiovascular disease, observing increased expression of transmembrane insulin receptor/insulin-like growth factor 1 receptor (IR/IGF1R) hybrid receptors and intracellular protein tyrosine kinase 2ß (PYK2) proteins. IR/IGF1R hybrids are composed of one IR and IGF1R a- and ß-subunit. Unlike their homodimeric counterparts, the physiological function of hybrids is yet unknown however, their ability to activate insulin signalling pathways is markedly reduced. Small molecule inhibitors have been identified and validated through rounds of iterative screening. Compound HI-2 has been shown to selectively inhibit the formation of hybrid receptors in human umbilical vein (HUVEC) and saphenous vein endothelial cells (SVEC). The effect of reducing hybrids using HI-2 has resulted in altered insulin signalling and wound healing. Autophosphorylation of PYK2 Y402 can inhibit endothelial nitric oxide synthase (eNOS) enzymatic activity by phosphorylation of its Y657 site and, subsequently reduces production of NO. Characterisation of the eNOS-PYK2 interaction has been demonstrated in HUVEC, SVEC and ATEC using coimmunoprecipitation and proximity ligation assays. Biophysical techniques such as surface plasmon resonance have been employed, however further method development is required. Inhibition of PYK2 using siRNA knockdown in HUVEC has shown a 45% reduction in expression; inhibition using pharmacological inhibitor, PF-10e in vitro and in vivo has not been effective. Molecular dynamics simulations have been employed in modelling proteinprotein interactions utilizing a coarse-grained/atomistic (CGAT) hybrid simulation method. A series of apo-IR, IGF1R and IR/IGF1R hybrid receptor models have been produced and simulations of each have been performed on the ARC3 high-performance computer server, at the University of Leeds. Characterisation of these interactions through biochemical, biophysical and computational techniques have contributed to a larger understanding of their mode of action, and subsequently highlighted their potential for modulation for therapeutic benefit. Further investigation is required to elucidate these interactions and design novel small molecule inhibitors for in vivo use.