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We report on the development and validation of a new version of DOCK. The algorithm has been rewritten in a modular format, which allows for easy implementation of new scoring functions, sampling methods and analysis tools. We validated the sampling algorithm with a test set of 114 protein-ligand complexes. Using an optimized parameter set, we are able to(More)
We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes of the active site flaps. In particular, the unliganded protease undergoes multiple conversions between the "closed" and "semiopen" forms observed in crystal structures of inhibitor-bound and unliganded protease, respectively, including(More)
Fatty acid binding proteins (FABPs), in particular FABP5 and FABP7, have recently been identified by us as intracellular transporters for the endocannabinoid anandamide (AEA). Furthermore, animal studies by others have shown that elevated levels of endocannabinoids resulted in beneficial pharmacological effects on stress, pain and inflammation and also(More)
With an increasing interest in RNA therapeutics and for targeting RNA to treat disease, there is a need for the tools used in protein-based drug design, particularly DOCKing algorithms, to be extended or adapted for nucleic acids. Here, we have compiled a test set of RNA-ligand complexes to validate the ability of the DOCK suite of programs to successfully(More)
In conjunction with the recent American Chemical Society symposium titled "Docking and Scoring: A Review of Docking Programs" the performance of the DOCK6 program was evaluated through (1) pose reproduction and (2) database enrichment calculations on a common set of organizer-specified systems and datasets (ASTEX, DUD, WOMBAT). Representative baseline grid(More)
Absolute free energies of hydration (ΔGhyd) for more than 500 neutral and charged compounds have been computed, using Poisson-Boltzmann (PB) and Generalized Born (GB) continuum methods plus a solvent-accessible surface area (SA) term, to evaluate the accuracy of eight simple point-charge models used in molecular modeling. The goal is to develop improved(More)
Point mutations in the influenza virus enzyme neuraminidase (NA) have been reported that lead to dramatic loss of activity for known NA inhibitors including the FDA approved sialic acid mimics zanamivir and oseltamivir. A more complete understanding of the molecular basis for such resistance is a critical component toward development of improved(More)
Matrix metalloproteinases (MMPs) represent a potentially important class of therapeutic targets for the treatment of diseases such as cancer. Selective inhibition of MMPs will be required given the high sequence identity across the family and the discovery that individual MMPs also regulate the natural angiogenesis inhibitor angiostatin. In this study, we(More)
The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis. The mammalian brain expresses three FABP(More)
The interactions and energetics associated with the binding of 20 HEPT and 20 nevirapine nonnucleoside inhibitors of HIV-1 reverse transcriptase (RT) have been explored in an effort to establish simulation protocols and methods that can be used in the development of more effective anti-HIV drugs. Using crystallographic structures as starting points, all 40(More)