Most human diseases have genetic components, frequently single nucleotide variants (SNVs), which alter the wild type characteristics of macromolecules and their interactions. A straightforward approach for correcting such SNVs-related alterations is to seek small molecules, potential drugs, that can eliminate disease-causing effects. Certain disorders are caused by altered protein-protein interactions, for example, Snyder-Robinson syndrome, the therapy for which focuses on the development of small molecules that restore the wild type homodimerization of spermine synthase. Other disorders originate from altered protein-nucleic acid interactions, as in the case of cancer; in these cases, the elimination of disease-causing effects requires small molecules that eliminate the effect of mutation and restore wild type p53-DNA affinity. Overall, especially for complex diseases, pathogenic mutations frequently alter macromolecular interactions. This effect can be direct, i.e., the alteration of wild type affinity and specificity, or indirect via alterations in the concentration of the binding partners. Here, we outline progress made in methods and strategies to computationally identify small molecules capable of altering macromolecular interactions in a desired manner, reducing or increasing the binding affinity, and eliminating the disease-causing effect. When applicable, we provide examples of the outlined general strategy. Successful cases are presented at the end of the work.