Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores

Computational modeling of inhibitors for metalloenzymes in virtual drug development campaigns has proven challenging. To overcome this limitation, a technique for predicting the binding pose of metal-binding pharmacophores (MBPs) is presented. Using a combination of density functional theory (DFT) calculations and docking using a genetic algorithm, inhibitor binding was evaluated in silico and compared with inhibitor-enzyme cocrystal structures. The predicted binding poses were found to be consistent with the cocrystal structures. The computational strategy presented represents a useful tool for predicting metalloenzyme-MBP interactions

Evaluation of 3‑Dimensionality in Approved and Experimental Drug Space

The 3-dimensional (3D) structure of therapeutics and other bioactive molecules is an important factor in determining the strength and selectivity of their protein-ligand interactions. Previous efforts have considered the strain introduced and tolerated through conformational changes induced upon protein binding. Herein, we present an analysis of 3-dimentionality for energy-minimized structures from the DrugBank and ligands bound to proteins identified in the Protein Data Bank (PDB). This analysis reveals that the majority of molecules found in both the DrugBank and the PDB tend toward linearity and planarity, with few molecules having highly 3D conformations. Decidedly 3D geometries have been historically difficult to achieve, likely due to the synthetic challenge of making 3D organic molecules, and other considerations, such as adherence to the 'rule-of-five'. This has resulted in the dominance of planar and/or linear topologies of the molecules described here. Strategies to address the generally flat nature of these data sets are explored, including the use of 3D organic fragments and inorganic scaffolds as a means of accessing privileged 3D space. This work highlights the potential utility of libraries with greater 3D topological diversity so that the importance of molecular shape to biological behavior can be more fully understood in drug discovery campaigns

Photorelease of a metal-binding pharmacophore from a Ru( ii ) polypyridine complex

The adoption of compounds that target metalloenzymes comprises a relatively low (<5%) percentage of all FDA approved therapeutics. Metalloenzyme inhibitors typically coordinate to the active site metal ions and therefore contain ligands with charged or highly polar functional groups. While these groups may generate highly water-soluble compounds, this functionalization can also limit their pharmacological properties. To overcome this drawback, drug candidates can be formulated as prodrugs. While a variety of protecting groups have been developed, increasing efforts have been devoted towards the use of caging groups that can be removed upon exposure to light to provide spatial and temporal control over the treatment. Among these, the application of Ru(ii) polypyridine complexes is receiving increased attention based on their attractive biological and photophysical properties. Herein, a conjugate consisting of a metalloenzyme inhibitor and a Ru(ii) polypyridine complex as a photo-cage is presented. The conjugate was designed using density functional theory calculations and docking studies. The conjugate is stable in an aqueous solution, but irradiation of the complex with 450 nm light releases the inhibitor within several minutes. As a model system, the biochemical properties were investigated against the endonucleolytic active site of the influenza virus. While showing no inhibition in the dark in an in vitro assay, the conjugate generated inhibition upon light exposure at 450 nm, demonstrating the ability to liberate the metalloenzyme inhibitor. The presented inhibitor-Ru(ii) polypyridine conjugate is an example of computationally-guided drug design for light-activated drug release and may help reveal new avenues for the prodrugging of metalloenzyme inhibitors

Metal complexes for therapeutic applications

Metal complexes have been widely used for applications in the chemical and physical sciences due to their unique electronic and stereochemical properties. For decades the use of metal complexes for medicinal applications has been postulated and demonstrated. The distinct characteristics of metal complexes, including their molecular geometries (that are not readily accessed by organic molecules), as well as their ligand exchange, redox, catalytic, and photophysical reactions, give these compounds the potential to interact and react with biomolecules in unique ways and by distinct mechanisms of action. Herein, the potential of metal complexes to act as components bioactive therapeutic compounds is discussed

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein–inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.

Fragment-based drug discovery (FBDD) is a powerful strategy for the identification of new bioactive molecules. FBDD relies on fragment libraries, generally of modest size, but of high chemical diversity. Although good chemical diversity in FBDD libraries has been achieved in many respects, achieving shape diversity - particularly fragments with three-dimensional (3D) structures - has remained challenging. A recent analysis revealed that >75% of all conventional, organic fragments are predominantly 1D or 2D in shape. However, 3D fragments are desired because molecular shape is one of the most important factors in molecular recognition by a biomolecule. To address this challenge, the use of inert metal complexes, so-called 'metallofragments' (mFs), to construct a 3D fragment library is introduced. A modest library of 71 compounds has been prepared with rich shape diversity as gauged by normalized principle moment of inertia (PMI) analysis. PMI analysis shows that these metallofragments occupy an area of fragment space that is unique and highly underrepresented when compared to conventional organic fragment libraries that are comprised of orders of magnitude more molecules. The potential value of this metallofragment library is demonstrated by screening against several different types of proteins, including an antiviral, an antibacterial, and an anticancer target. The suitability of the metallofragments for future hit-to-lead development was validated through the determination of IC50 and thermal shift values for select fragments against several proteins. These findings demonstrate the utility of metallofragment libraries as a means of accessing underutilized 3D fragment space for FBDD against a variety of protein targets

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.

Fragment-based drug discovery (FBDD) is a powerful strategy for the identification of new bioactive molecules. FBDD relies on fragment libraries, generally of modest size, but of high chemical diversity. Although good chemical diversity in FBDD libraries has been achieved in many respects, achieving shape diversity - particularly fragments with three-dimensional (3D) structures - has remained challenging. A recent analysis revealed that >75% of all conventional, organic fragments are predominantly 1D or 2D in shape. However, 3D fragments are desired because molecular shape is one of the most important factors in molecular recognition by a biomolecule. To address this challenge, the use of inert metal complexes, so-called 'metallofragments' (mFs), to construct a 3D fragment library is introduced. A modest library of 71 compounds has been prepared with rich shape diversity as gauged by normalized principle moment of inertia (PMI) analysis. PMI analysis shows that these metallofragments occupy an area of fragment space that is unique and highly underrepresented when compared to conventional organic fragment libraries that are comprised of orders of magnitude more molecules. The potential value of this metallofragment library is demonstrated by screening against several different types of proteins, including an antiviral, an antibacterial, and an anticancer target. The suitability of the metallofragments for future hit-to-lead development was validated through the determination of IC50 and thermal shift values for select fragments against several proteins. These findings demonstrate the utility of metallofragment libraries as a means of accessing underutilized 3D fragment space for FBDD against a variety of protein targets