Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.

Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein.

Identification and validation of modulators of exchange protein activated by cAMP (Epac) activity: structure-function implications for Epac activation and inhibition.

The signaling molecule cAMP primarily mediates its effects by activating PKA and/or exchange protein activated by cAMP (Epac). Epac has been implicated in many responses in cells, but its precise roles have been difficult to define in the absence of Epac inhibitors. Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is directly activated by cAMP.

Variational Implicit-Solvent Modeling of Host-Guest Binding: A Case Study on Cucurbit[7]uril|.

The synthetic host cucurbit[7]uril (CB[7]) binds aromatic guests or metal complexes with ultrahigh affinity compared with that typically displayed in protein-ligand binding. Due to its small size, CB[7] serves as an ideal receptor-ligand system for developing computational methods for molecular recognition. Here, we apply the recently developed variational implicit-solvent model (VISM), numerically evaluated by the level-set method, to study hydration effects in the high-affinity binding of the B2 bicyclo[2.

Comparing neural-network scoring functions and the state of the art: applications to common library screening.

We compare established docking programs, AutoDock Vina and Schrödinger's Glide, to the recently published NNScore scoring functions. As expected, the best protocol to use in a virtual-screening project is highly dependent on the target receptor being studied. However, the mean screening performance obtained when candidate ligands are docked with Vina and rescored with NNScore 1.

On the Role of Dewetting Transitions in Host-Guest Binding Free Energy Calculations.

We use thermodynamic integration (TI) and explicit solvent molecular dynamics (MD) simulation to estimate the absolute free energy of host-guest binding. In the unbound state, water molecules visit all of the internally accessible volume of the host, which is fully hydrated on all sides. Upon binding of an apolar guest, the toroidal host cavity is fully dehydrated; thus, during the intermediate λ stages along the integration, the hydration of the host fluctuates between hydrated and dehydrated states.

Novel cruzain inhibitors for the treatment of Chagas' disease.

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T.