AbstractWe consider the problem of predicting the mode of binding of a small molecule to a receptor site on a protein. One plausible approach, given a rigid molecule and its geometry, is to search directly for the orientation in space that maximizes the degree of contact. The computation time required for such a naive procedure is proportional ton3m3, wherenis the number of points in the site where binding can occur, andmis the number of atoms in the ligand. We give an alternative, combinatorial approach, in which only “contact–no‐contact” criteria are considered. We relate this problem to the well‐known combinatorial problem of finding cliques in a graph and show that we can use a solution to the clique problem not only to solve our original problem, but also the problem of avoiding energetically unfavorable matches. Our experience with this method indicates that the computation time required is proportional tonm2.8, with a lower constant of proportionality than that of the naive