The growing resistance of the influenza virus to widely used competitive neuraminidase inhibitors occupying the active site of the enzyme requires the development of bifunctional compounds that can simultaneously interact with other regulatory sites on the protein surface. When developing such an inhibitor and combining structural fragments that could be located in the sialic acid cavity of the active site and the adjacent 430-cavity, it is necessary to select a suitable linker not only for connecting the fragments, but also to ensure effective interactions with the unique arginine triad Arg118-Arg292-Arg371 of neuraminidase. Using molecular modeling, we have demonstrated the usefulness of the sulfonamide group in the linker design and the potential advantage of this functional group over other isosteric analogues.

The development of novel small drug molecules is a complex and important cross-disciplinary task. In the early stages of development, chemoinformatics and bioinformatics methods are routinely used to reduce the cost of finding a lead compound. Among the tools of medicinal chemistry, docking and molecular dynamics occupy a special place. These methods are used to predict the possible mechanism of binding of a potential ligand to a protein target. However, in order to perform a docking study, it is necessary to know the spatial structure of the protein under investigation. Although databases of crystallographic structures are available, the three-dimensional representations of many protein molecules have not been reported. There is therefore a need to model such three-dimensional conformations. Several computer algorithms have been published to solve this problem. AlphaFold is considered by the scientific community to be the most effective approach to predicting the three-dimensional structure of proteins. However, the scope of its application in medicinal chemistry, especially for virtual screening, remains unclear. This review describes methods for predicting the three-dimensional structure of a protein and provides representative examples of the use of AlphaFold for the design and rational selection of potential ligands. Special attention is given to publications presenting the results of experimental validation of the approach. On the basis of performed analysis, the main problems in the field and possible ways to solve them are formulated. The bibliography includes 154 references.

IntroductionThe ataxia telangiectasia mutated kinase (ATM) is key in coordinating the DDR signaling network essential for responding to double-strand breaks (DSBs). Several ATM inhibitors are being investigated for potential anticancer treatment in clinical trials.Areas coveredThis review aims to provide a comprehensive overview of patents and patent applications since 2003, with a particular focus on the structural properties, activity and efficacy of the claimed ATM kinase small-molecule inhibitors. The search was conducted using SciFinder, Cortellis Drug Discovery Intelligence Database, and Espacenet. After filtering, 44 records were identified for further analysis. This paper also discusses the recent progress in the clinical trials and development history.Expert opinionATM kinase is a promising target for cancer therapy. Small-molecule ATM kinase inhibitors hold significant potential in cancer treatment by enhancing the efficacy of existing DNA-damaging therapies. Patent analysis revealed that the majority of these compounds contain imidazo[4,5-c]quinolinone scaffold or its bioisosteric variations which are optimal in terms of good ATM inhibitory activity and selectivity over closely related enzymes. Clinical trials explore combinations with RT or DNA-targeted compounds like PARP inhibitors, which induce DSBs. The medicinal chemistry field anticipates that these therapeutic options will soon be available on the pharmaceutical market.