Molecular binding in structure-based drug design: a case study of the population-based annealing genetic algorithms

The molecular binding problem, one of the most important problems in structure based drug design, can be formulated as a global energy optimization problem by using molecular mechanics. A novel computational algorithm is proposed to address the molecular binding problem. The algorithm is derived from genetic algorithms (GA) plus simulated annealing (SA) hybrid techniques, namely population based annealing genetic algorithms (PAG). We have applied the algorithm to find binding structures for three drug protein molecular pairs. One of the three drugs is an anti cancer drug methotrexate (MTX) and the other two are analogues of the antibacterial drug trimethoprim. Moreover, we have also studied two other well resolved ligand receptor molecular complex which are obtained from the Protein Data Bank (PDB): Thermolysin-HONH-benzylmalonyl-L-Ala-Gly-p-nitroanilide complex (5tln) and HIV-1 protease-Hydroxyethylene isostere inhibitor complex. Hydroxyethylene isostere inhibitor is one of new potential HIV-1 protease inhibitors synthesized. Through our experiments, all of the binding results not only keep the energy at low levels, but also have a promising binding geometrical structure in terms of number of hydrogen bonds formed.