erroneous interaction Tamoxifen potentials. In the absence of crystallographic data, docked structures that show strong correlations with in vitro activity are more likely to reflect the actual structures. The in vitro susceptibility data for WT IN and drug resistant mutants for RAL, EVG, MK 0536, and DTG correlate well with the calculations. The corresponding in vitro data for XZ89, CHI 1043, and INSTI 1 against drug resistant IN mutants are not available. Crystal structures and static models provide a snapshot of what is taking place in a molecular system. Basing an energy calculation on a single structure raises the possibility of error due to relatively minor discrepancies in the structure. Our calculations each lude data for 100 similar variations resulting from the bond rotation and oscillation introduced by the MD simulation.
This should compensate for two potential sources of error. First, side chains or entire secondary structure elements could be influenced by crystal Estrogen Receptor Pathway packing contacts. Second, crystal packing could directly influence the orientation of the ligand or cause indirect influence via contacts with a neighboring protein residue. Either of these cases could perturb the interaction and introduce error into the calculation. Monitoring the results of Hamiltonian equations through the simulation shows that the system is sufficiently equilibrated after 50.0 ps , and averaging the 100 instantaneous interaction potential values obtained after that time point gives a result that closely correlates with the in vitro activity of the compounds.
conserved nature of the CA dinucleotide, optimizing this interaction could be a significant factor objectified in future INSTI development. The binding energy calculations described here are limited in that the displaced adenosine must be in the correct orientation to obtain accurate values. Although it is possible that the adenosine’s multiple conformations mean that its interactions with the INSTIs are relatively weak, crystal structures of the PFV IN INSTI complex would be quite helpful in refining the calculations. Fortunately, the process of obtaining PFV IN crystals is developing at a rapid pace and structures of additional interesting compounds should be available in the near future. Crystallographic data and this MD approach in an HIV 1 IN model should provide valuable new details regarding INSTI binding that could lead to the development of more effective INSTIs and novel scaffolds.
Crystal structures of all four compounds bound to the PFV intasome have been solved . Three additional compounds were tested for which neither structural data nor activities against the mutants are available. Shown in Fig. 1, XZ89 and CHI 1043 are structurally distt from any of the four compounds used to verify theMDapproach . INSTI 1 is similar to RAL . The range of the means of the interaction potentials calculated for these three compounds all overlapped our reference curve at the respective IC50s for each compound, and the most active of the three was clearly identified . This result is particularly promising because it shows that estimated IC50s correlate with experimentally determined values even when structural data are not available. orporating novel mutations into this model before crystal structures .