To help overcome challenges in developing kinase inhibitors, many computational methods have been developed over the last few decades, either to complement experimental findings or to forecast kinase inhibitor activity and selectivity. This review provides insight into recent advances in theoretical/computational approaches for the design of new kinase inhibitors with the desired selectivity and optimization of existing inhibitors.

Abstract

Kinases are prominent drug targets in the pharmaceutical and research community due to their involvement in signal transduction, physiological responses, and upon dysregulation, in diseases such as cancer, neurological and autoimmune disorders. Several FDA-approved small-molecule drugs have been developed to combat human diseases since Gleevec was approved for the treatment of chronic myelogenous leukemia. Kinases were considered “undruggable” in the beginning. Several FDA-approved small-molecule drugs have become available in recent years. Most of these drugs target ATP-binding sites, but a few target allosteric sites. Among kinases that belong to the same family, the catalytic domain shows high structural and sequence conservation. Inhibitors of ATP-binding sites can cause off-target binding. Because members of the same family have similar sequences and structural patterns, often complex relationships between kinases and inhibitors are observed. To design and develop drugs with desired selectivity, it is essential to understand the target selectivity for kinase inhibitors. To create new inhibitors with the desired selectivity, several experimental methods have been designed to profile the kinase selectivity of small molecules. Experimental approaches are often expensive, laborious, time-consuming, and limited by the available kinases. Researchers have used computational methodologies to address these limitations in the design and development of effective therapeutics. Many computational methods have been developed over the last few decades, either to complement experimental findings or to forecast kinase inhibitor activity and selectivity. The purpose of this review is to provide insight into recent advances in theoretical/computational approaches for the design of new kinase inhibitors with the desired selectivity and optimization of existing inhibitors.

The large and highly branched antitumor homoharringtonine, here in black sticks, owing to its conformationally mobile nature can interact with a variety of nucleotides at site A of the ribosome PCT, like in a spider web.

Abstract

Modified nucleotides are ubiquitous with RNAs, also in contact with drugs that target the ribosome. Whether this represents a stabilization of the drug-ribosome complex, thus affecting the drug's affinity and possibly also intrinsic efficacy, remains an open question, however. The challenge of answering this question has been taken here with the only human-ribosome-targeting small-molecule currently in clinical use, the antitumor plant alkaloid homoharringtonine (HHT). The approach consisted in dissecting HHT-nucleotide interaction energies from QM-MM simulations in explicit water. What emerged is a network of mostly weak interactions of the large, branched HHT with standard nucleotides and a single modified nucleotide, out of the four ones present at PCT's A site. This is unlike the case of the small, compact marine antitumor alkaloid agelastatin A, which displays only a few, albeit strong, interactions with site-A ribosome nucleotides. This should aid tailoring drugs targeting the ribosome.

Ru-based antibacterial agents, which can kill bacteria by releasing ROS and damaging bacterial cell membrane integrity, were developed. Ru (II)-1 not only showed low toxicity, but also has strong antibacterial potency against S. aureus in vivo.

Abstract

The development of antimicrobial agents with novel model of actions is a promising strategy to combat multiple resistant bacteria. Here, three ruthenium-based complexes, which acted as potential antimicrobial agents, were synthesized and characterized. Importantly, three complexes all showed strong bactericidal potency against Staphylococcus aureus. In particular, the most active one has a MIC of 6.25 μg/mL. Mechanistic studies indicated that ruthenium complex killed S. aureus by releasing ROS and damaging the integrity of bacterial cell membrane. In addition, the most active complex not only could inhibit the biofilm formation and hemolytic toxin secretion of S. aureus, but also serve as a potential antimicrobial adjuvant as well, which showed synergistic effects with eight traditional antibiotics. Finally, both G. mellonella larva infection model and mouse skin infection model all demonstrated that ruthenium complex also showed significant efficacy against S. aureus in vivo. In summary, our study suggested that ruthenium-based complexes bearing a phenyl hydroxide are promising antimicrobial agents for combating S. aureus.

One quinazolin-2,4,6-triamine derivative was found to be a better bovine xanthine oxidase (bXO) inhibitor than allopurinol. Three quinazoline derivatives were not micronuclei inducers in a murine model. Three quinazolin-2,4,6-triamine derivatives acted as superoxide scavengers, and one 5,6-dihydro-3H-pirimidin-4-one showed bXO inhibitory activity.

Abstract

In this work, a new set of quinazolin-2,4,6-triamine derivatives were synthesized to explore their potential biological activity as xanthine oxidase (XO) inhibitors, superoxide scavengers and screening of their toxicological profile. Among all the synthesized compounds, B1 exhibited better inhibitory activity against bovine xanthine oxidase (bXO) than allopurinol (IC₅₀=1.56 μM and IC₅₀=6.99 μM, respectively). As superoxide scavengers, B1, B2 and B13 exhibited a better effect than allopurinol (97.3 %, 82.1 %, 87.4 % and 69.4 %, respectively). Regarding the toxicological profile, B1 was less cytotoxic than methotrexate on HCT-15 cancer cells. Apoptosis results obtained in cells of female and male mice, showed that B1 and B2 presented a similar behaviour to CrO₃ (positive control) with respect to the average frequency to induce apoptosis; while B13 apoptosis induced effect was similar to DMSO and control group. Finally, B1, B2, B13 did not induce genotoxicity in a micronuclei murine model compared to CrO₃.

Systematically substituting dip for phen or bpy ligands leads to a sudden spike in uptake and cytotoxicity as well as cytoskeletal localization in MCF7 and H358 cells, once two or more dip ligands are present. The most potent complexes are associated with those that best promote tubulin polymerizations, supporting this as the cellular target.

Abstract

Ruthenium(II) trisdiimine complexes of the formula, [Ru(dip)_n(L−L)_3-n]²⁺, where n=0-3; dip=4,7-diphenyl-1,10-phenanthroline; L–L=2,2’-bipyridine (bpy) or 1,10-phenanthroline (phen) were prepared and tested for cytotoxicity in two cell lines (H358, MCF7). Cellular uptake and subcellular localization were determined by harvesting treated cells and determining the ruthenium concentration in whole or fractionated cells (cytosolic, nuclear, mitochondrial/ ER/Golgi, and cytoskeletal proteins) by Ru ICP-MS. The logP values for the chloride salts of these complexes were measured and the data were analyzed to determine the role of lipophilicity versus structure in the various biological assays. Cellular uptake increased with lipophilicity but shows the biggest jump when the complex contains two or more dip ligands. Significantly, preferential cytoskeletal localization is also correlated with increased cytotoxicity. All of the RPCs promote tubulin polymerization in vitro, but [Ru(dip)₂phen]²⁺ and [Ru(dip)₃]²⁺ show the strongest activity. Analysis of the pellet formed by centrifugation of MTs formed in the presence of [Ru(dip)₂phen]²⁺ establish a binding stoichiometry of one RPC per tubulin heterodimer. Complexes of the general formula [Ru(dip)₂(L−L)]²⁺ possess the necessary characteristics to target the cytoskeleton in live cells and increase cytotoxicity, however the nature of the L−L ligand does influence the extent of the effect.

This highlight features a recently reported rational construction of antioxidase-like active site, Mn-N₅, having axial ligands and 2D d-π-conjugated network that robustly scavenge reactive oxygen species and provide cytoprotection to stem cells and transcription of osteogenesis-related genes.

Abstract

Reactive oxygen species (ROS) refer to various partially reduced oxygen moieties that are naturally generated due to biochemical processes. Elevated formation of ROS leads to damage to biomolecules, resulting in oxidative stress and cell death. The increased level of ROS also affects therapeutics based on stem cell transplantation. Nanomaterials-based enzyme mimetics have attracted immense attention, but there are several challenges to be addressed in terms of selectivity, efficiency, and biocompatibility. This highlight focuses on a recent investigation by Cheng and coworkers, who engineered an Mn-superoxide dismutase (Mn-SOD)-inspired material with Mn-N₅ sites having an axial ligand and 2D d-π-conjugated network. This engineering approach enhances antioxidase-like function and effectively rescues stem cells from ROS. In addition, it also protects osteogenesis-related gene transcription, ensuring survival rates and osteogenic differentiation of hMSCs under ROS environment. This versatile and robust artificial antioxidase holds promise for stem cell therapies and ROS-originated diseases.

Molecular fragmentation has been frequently used for machine learning, molecular modeling, and drug discovery studies. However, the current molecular fragmentation tools often lead to large fragments that are useful to limited tasks. Specifically, long aliphatic chains, certain connected ring structures, fused rings, as well as various nitrogen-containing molecular entities often remain intact when using BRICS. With no known methods to solve this issue, we find that the fragments taken from BRICS are inflexible for tasks such as fragment-based machine learning, coarse-graining, and ligand-protein interaction assessment. In this work, we develop a revised BRICS (r-BRICS) module that allows more flexible fragmentation on a wider variety of molecules. We show that r-BRICS generates smaller fragments than BRICS, allowing localized fragment assessments. Furthermore, r-BRICS generates a fragment database with significantly more unique small fragments than BRICS, which is potentially useful for fragmentbased drug discovery.

We developed a linear variant of the potent cytotoxic (−)-zampanolide that retains nanomolar activity towards cancer cell lines. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity. High-field 2D-NMR, computational modeling, and antiproliferative assays were utilized to develop the conformation-activity relationship profile for this class of marine polyketide. This successful design strategy now provides three new sites for further analogue development; N-acyl hemiaminal side chain, C19 acyl group, and C9 ketone.

Abstract

Through an understanding of the conformational preferences of the polyketide natural product (−)-zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a set of three structural handles for further structure-activity relationship (SAR) studies of this potent microtubule-stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.