Dynamic ligand design

This category includes genetic algorithm methods,CONCEPTS, CONCERTS, the dynamic ligand design (OLD) approach, MCDNLG, 64 and Hahn s RECEPTOR program. ... 

A. Miranker and M. Karpins, Proteins Struct., Funct., Genet., 23, 472 (1995). An Automated-Method for Dynamic Ligand Design. 

CAESA = Computer Assisted Estimation of Synthetic Accessibility CSD = Cambridge Structural Database DLD = dynamic ligand design FEP = free energy perturbation MCSS = maximum common substructure PDB = Protein Data Bank. 

DA Pearlman, MA Murcko (1996) CONCERTS Dynamic Connection of Fragments as an Approach to de Novo Ligand Design, J Med Chem 39(8) 1651—1663... 

Similarly, a choice had to be made regarding the topics covered in this volume. For example, molecular dynamics (MD) based free-energy changes in solution calculations are not treated, because these are not yet a day-to-day practice in actual ligand design due to the very high computational demands for the long MD simulations required. 

In the second example, in which desolvation influences were considered, Reddy et al. used a computer-assisted ligand design method that combines molecular mechanics, molecular dynamics, FEP calculations, synthesis, and biochemical testing of peptidomimetic inhibitors, plus crystallographic structure determination of the protein-inhibitor complexes. This combination of techniques successfully led to the design of novel inhibitors for the HIV-1 protease enzyme. This study involved a large set of molecules whose relative binding affinities, predicted via the FEP method prior to synthesis, were later confirmed by experimental measurements. 

In principle, simulated annealing (SA) provides another methodology for ligand design. Conformational searching with SA-based methods is efficient compared with traditional molecular dynamics methods. " Further, SA can be combined with other techniques such as stochastic dynamics for greater efficiency. For example. Hart and Read combined a Monte Carlo approach with SA (described below). Also, Yue has demonstrated the ability to find bound conformations with SA. ... 

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