A technique to study molecular recognition in drug design: Preliminary application of free energy derivatives to inhibition of a malarial cysteine protease

Abstract

We present molecular dynamics studies on model complexes of inhibitors of a malarial cysteine protease. The initial model for such complexes came from the model building of the protein using its homology with other cysteine proteases and calculations using DOCK to generate new lead compounds. Some of the initial model-built structures were quite stable for 100 psec of dynamics; others moved significantly from their model-built orientation. We also calculated the free energy derivatives at each atom in the inhibitor, both in water and in the binding site. The results of these calculations suggest directions for the design of new, more potent enzyme inhibitors and agree qualitatively with some of the experimental findings. Nonetheless, we stress that we have only used this methodology in an interpretive rather than a predictive manner.

The catalytic site structural gate of adenosine deaminase allosterically modulates ligand binding to adenosine receptors

“…These two structures were used to generate starting models for MD simulations in both holo and apo forms (obtained by removing ligands). For this purpose, the monomeric crystal structure was fully solvated with an octahedron tip3p water box; ions were added, and final system was minimized and equilibrated to 300 K using amber force field (41) and implemented in the NAMD program (42, 43). Finally, 100 ns of production were collected in the isothermicisobaric ( P =1 atm, T = 298 K).…”

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

“…Cieplak, P. and co-workers [135] performed one of the first and few MD studies on model complexes of FPs inhibitors. In their work, classical MD was used as a filter for evaluating proposed binding modes.…”

Designing molecular complexes using free-energy derivatives from liquid-state integral equation theory

“…For instance, locally changing a site charge and/or apolar atomic size/interaction strength parameters can be viewed as virtual substitutions on otherwise unchanged scaffolds, for which a derivative can be mathematically defined. Such a concept of deriving a FED based on free-energy MD simulations was proposed more than two decades ago by several authors [7][8][9], and has been further explored with more or less promising results [10][11][12]. In a related approach, van Gunsteren et al have devised methods to compute free-energy changes simultaneously for several target states (representing different chemistries) from simulation of only a single reference system [13,14].…”