Identification of potential hit compounds for Dengue virus NS2B/NS3 protease inhibitors by combining virtual screening and binding free energy calculations.

Dengue virus (DV) infections are a serious public health problem and there is currently no vaccine or drug treatment. NS2B/NS3 protease, an essential enzyme for viral replication, is one of the promising targets in the search for drugs against DV. In this research work, virtual screening (VS) was carried out on four multi-conformational databases using several criteria. Firstly, molecular dynamics simulations of the NS2B/NS3 protease and four known inhibitors, which reveal an importance of both electrostatic and van der Waals interactions in stabilizing the ligand-enzyme interaction, were used to generate three different pharmacophore models (a structure-based, a static and a dynamic). Subsequently, these three models were employed for pharmacophore search in the VS. Secondly, compounds passing the first criterion were further reduced using the Lipinski's rule of five to keep only compounds with drug-like properties. Thirdly, molecular docking calculations were performed to remove compounds with unsuitable ligand-enzyme interactions. Finally, binding free energy of each compound was calculated. Compounds having better energy than the known inhibitors were selected and thus 20 potential hits were obtained.

Comparative molecular field analysis of artemisinin derivatives: ab initio versus semiempirical optimized structures.

Based on the belief that structural optimization methods, producing structures more closely to the experimental ones, should give better, i.e. more relevant, steric fields and hence more predictive CoMFA models, comparative molecular field analyses of artemisinin derivatives were performed based on semiempirical AM1 and HF/3-21G optimized geometries. Using these optimized geometries, the CoMFA results derived from the HF/3-21G method are found to be usually but not drastically better than those from AM1. Additional calculations were performed to investigate the electrostatic field difference using the Gasteiger and Marsili charges, the electrostatic potential fit charges at the AM1 level, and the natural population analysis charges at the HF/3-21G level of theory. For the HF/3-21G optimized structures no difference in predictability was observed, whereas for AM1 optimized structures such differences were found. Interestingly, if ionic compounds are omitted, differences between the various HF/3-21G optimized structure models using these electrostatic fields were found.