Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors

Metalloenzymes are ubiquitous proteins which feature one or more metal ions either directly involved in the enzymatic activity and/or structural properties (i.e., zinc fingers). Several members of this class take advantage of the Lewis acidic properties of zinc ions to carry out their various catalytic transformations including isomerization or amide cleavage. These enzymes have been validated as drug targets for a number of diseases including cancer; however, despite their pharmaceutical relevance and the availability of crystal structures, structure-based drug design methods have been poorly and indirectly parametrized for these classes of enzymes. More specifically, the metal coordination component and proton transfers of the process of drugs binding to metalloenzymes have been inadequately modeled by current docking programs, if at all. In addition, several known issues, such as coordination geometry, atomic charge variability, and a potential proton transfer from small molecules to a neighboring basic residue, have often been ignored. We report herein the development of specific functions and parameters to account for zinc–drug coordination focusing on the above-listed phenomena and their impact on docking to zinc metalloenzymes. These atom-type-dependent but atomic charge-independent functions implemented into Fitted 3.1 enable the simulation of drug binding to metalloenzymes, considering an acid–base reaction with a neighboring residue when necessary with good accuracy

Design of 5’,7’-Dihydroxyflavones and β-D-Glucopyranosyl Heterocyclic Derivatives as Glycogen Phosphorylase Inhibitors

There has been a significant increase in the number of people diagnosed with diabetes from 1980 to 2016, rising from 108 million to approximately 420 million people worldwide, and is predicted to rise to above 640 million by the year 2040 and type II diabetes is seen in 90-95% of those diagnosed. Many treatments currently exist to treat type II diabetes, although there are considerable adverse health effects associated with these drugs including a risk of hypoglycaemia. Accordingly, there is a swift need for a new, effective treatment that has little to no side effect for those suffering from T2D. β-D-Glucopyranosyl derivatives are known to inhibit glycogen phosphorylase, which is a valid target for controlling hyperglycaemia in type 2 diabetes. Computational methods, such as molecular docking with Glide and GOLD as well as post-docking free energy calculations using MM-GBSA calculations were used to screen a library of β-D-glucopyranosyl analogues and we, for the first time, have derived computational models of MMGBSA for the GPb catalytic site have revealed excellent predictive potential based on a thorough statistical analysis. Using these models, correlations between predicted and experimental inhibitory potential as high as 0.95 – 0.97 were obtained for a training set of ligands. These methods have substantial potential for discovery of new effective compounds in the treatment of T2D as thousands of potential ligands could in the future be screened. Previous computational screening of 5,7-dihydroxyflavone analogues which have been predicted to bind at the caffeine binding site have been performed and a number of these analogues have been synthesized and will undergo kinetic experiments which will give insight into the effectiveness of 5’,7’-dihydroxyflavone derivatives so that a wider library of similar compounds could be tested that displays biological activity towards glycogen phosphorylase