In this paper, we have presented a detailed study of a local hard-soft acid-base (HSAB) principle for describing multiple-site interactions between the molecular systems. The local HSAB principle, which has been recently used to study single-site based interactions, can be generalized for the description of multiplesite-based interactions by different ways. We have elaborated these approaches and showed the validity of these models by making a detailed study on model prototype interactions that are relevant to biological molecular interaction processes. We discuss the nature of these approaches and the domain of their applicability.