A new fast computational method for mass calculations of docking complexes by the AM1/PM3 semiempirical methods is proposed. The computation time is shortened by at least an order of magnitude compared to alternative schemes of quantum chemical calculations. The root mean square deviation of the AM1 calculated energies of formation of complexes from the results obtained by conventional diagonalization procedure is at most 0.4 kcal mol -1 .Relationships between the biological activity and theoretical estimates of protein-ligand interaction ener gies can be used for prediction of activity, in particu lar, for solving topical tasks in drug design (see, e.g., Refs 1 and 2).Quantum chemical methods seem to be the most promising and versatile tool of estimation of proteinligand interaction energies and elucidaton of the geom etry and electronic structure of protein-ligand complexes. However, such methods can hardly be used for mass cal culations of practically interesting docking complexes comprised of a few thousand atoms each because of very high computational cost of the calculations of large mo lecular systems. 3,4Recently, a number of specific semiempirical 5,6 and ab initio 7,8 quantum chemical methods and programs for calculations of very large biomolecules were developed. Improved performance is, in particular, achieved by using quite rough approximations, which include fragmenta tion of molecules into small fragments, closure of the broken bonds, and mutual influence of the fragments in the framework of the additive scheme. 7,8 However, even in this case the performance is too low to carry out mass calculations of docking complexes. The quantum mechanical/molecular mechanics (QM/MM) methods 2,9-11 are used if only a small fragment of a complex requires the full QM treatment; the remaining part of the complex is calculated by the MM methods. As a result, the prob