A chemical, structural, molecular electrostatic potential (MEP) analysis of modified nucleosides allows the understanding of how nucleosides interact with different receptors. The interaction with kinases is sensitive to base modifications, while the interaction with the reverse transcriptase receptor HIV active site is more affected by ribose modifications. The model herein indicates a geometrical lower limit in the width of the modified sugar that corresponds to the 3' erythro position. This characteristic allows one to predict a potential activity of the 3' substituted compounds. The 4'-hydroxymethyl group position with respect to the nucleic base is also important for antiviral activity. The model gives the geometric parameters of this position (related to kinetic effects) that corresponds to an increase in the activation energy required to fit the active site of the kinases and the RT. Our model is compatible with the 3D structure of the HIV RT active site. It allows the design of potent new active compounds where the sugar can be substituted by any group answering to the defined parameters.