Current Topics in Medicinal Chemistry - Volume 16, Issue 4, 2016

Metalloproteins have attracted momentous attentions for the treatment of many human diseases, including cancer, HIV, hypertension, etc. This article reviews the progresses that have been made in the field of drug development of metalloprotein inhibitors, putting emphasis on the targets of carbonic anhydrase, histone deacetylase, angiotensin converting enzyme, and HIV-1 integrase. Many other important metalloproteins are also briefly discussed. The binding and coordination modes of different marketed metalloprotein inhibitors are stated, providing insights to design novel metal binding groups and further novel inhibitors for metalloproteins.

Methionine aminopeptidases (MetAPs) are metalloenzymes that cleave the N-terminal methionine from newly synthesized peptides and proteins. These MetAP enzymes are present in bacteria, and knockout experiments have shown that MetAP activity is essential for cell life, suggesting that MetAPs are good antibacterial drug targets. MetAP enzymes are also present in the human host and selectivity is essential. There have been significant structural biology efforts and over 65 protein crystal structures of bacterial MetAPs are deposited into the PDB. This review highlights the available crystallographic data for bacterial MetAPs. Structural comparison of bacterial MetAPs with human MetAPs highlights differences that can lead to selectivity. In addition, this review includes the chemical diversity of molecules that bind and inhibit the bacterial MetAP enzymes. Analysis of the structural biology and chemical space of known bacterial MetAP inhibitors leads to a greater understanding of this antibacterial target and the likely development of potential antibacterial agents.

HDAC inhibitors (HDACIs), which can be used to kill cancer cells through inhibiting histone deacetylase activity or altering the structure of chromatin, have emerged as efficacious agents in the treatment of cancer. With SAHA, FK228, belinostat and panobinostat approved by the FDA, displaying satisfying activity in both haematological and solid tumors of various tissues, efforts to create selective HDACIs have been attracted attention over the past several years. Herein, we mainly review the progress of selective HDAC inhibitors including class-selective and isoform-selective HDAC inhibitors.

Histone acetyl transferases (HATs) and histone deacetylases (HDACs) are antagonistic enzymes regulating the turnover of histone acetylation thereby governing gene expression in a precise manner. Histone acetylation deregulation caused by aberrant expression of classical HDACs plays a crucial role in tumour onset and progression making these enzymes as striking targets for anticancer drugs and therapy. Small molecule inhibitors targetting HDACs (HDACi) have shown multiple biological effects including cell cycle arrest, differentiation and apoptosis in cancer cell models. The current review deals with the recently approved pan-HDAC inhibitor panobinostat (LBH589) and its antiproliferative activity against distinct cancers (breast, ovarian, lung and multiple myeloma). The intricate details about the different mechanisms triggered by panobinostat to exert cytotoxic effect in these cancers have also been provided. The article also highlights the different combination strategies of panobinostat which can be utilized for overcoming conventional therapy resistant cases and for achieving the enhanced therapeutic benefit from this marvelous inhibitor in the upcoming future.

Integrase (IN) is an essential viral enzyme required for HIV-1 replication, which has been targeted by anti-AIDS therapeutics. Integrase strand transfer inhibitors (INSTIs) represent a new class of antiretroviral agents developed for the treatment of HIV-1 infections. Important structural features that are shared by many INSTIs include a coplanar arrangement of three heteroatoms that chelate two catalytic Mg2+ ions in the IN active site and a linked halophenyl ring that binds in the hydrophobic pocket formed by the complex of IN with viral DNA. We recently reported bicyclic 6,7-dihydroxyoxoisoindolin-1-one-based IN inhibitors. In the current study, we modified these inhibitors in three ways. First, we increased the spacer length between the metalchelating triad and the halophenyl group. Second, we replaced the indoline [5,6] bicycle with a fused dihydroxyisoquinolinones [6,6] ring system. Finally, we prepared bis-6,7-dihydroxyisoindolin-1-one-4-sulfonamides as dimeric HIV-1 IN inhibitors. These new analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays.

HIV-1 integrase (IN) plays an important role in the life cycle of HIV and is responsible for integration of the virus into the human genome. We present computational approaches used to design novel HIV-1 IN inhibitors. We created an IN inhibitor database by collecting experimental data from the literature. We developed quantitative structure-activity relationship (QSAR) models of HIV-1 IN strand transfer (ST) inhibitors using this database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as with an additional validation set of 308 structurally distinct compounds from the publicly accessible BindingDB database. The validated models were used to screen a small combinatorial library of potential synthetic candidates to identify hits, with a subsequent docking approach applied to further filter out compounds to arrive at a small set of potential HIV-1 IN inhibitors. As result, 236 compounds with good druglikeness properties and with correct docking poses were identified as potential candidates for synthesis. One of the six compounds finally chosen for synthesis was experimentally confirmed to inhibit the ST reaction with an IC50(ST) of 37μM. The IN inhibitor database is available for download from http://cactus.nci.nih.gov/download/iidb/.

Matrix metalloproteinases (MMPs) are zinc enzymes responsible for the degradation of the extracellular matrix. With this function, MMPs are involved in many physiological processes, but also in many pathological states. MMP-13 is implicated in the degradation of type II collagen, the main structural protein of articular cartilage, contributing to the development of osteoarthritis and inflammatory diseases. In the last years, a new generation of potent and selective MMP inhibitors (MMPIs) has been identified and classified as non-zinc-binding inhibitors (NZBIs). Several MMP-13 NZBIs have been developed and crystallographically determined in complex with the enzyme. Here, we provide a detailed review of the current knowledge about this class of MMP-13 inhibitors and, by using computational procedures, we highlight the molecular determinants that are needed for the binding process. In particular, FLAP, a program based on GRID molecular interaction fields, was used to analyze the ligand-protein interactions: molecular shape and hydrogen bond acceptor groups strongly influence the binding according to the ligand-based modeling, while the aromatic interactions are better identified by the structure-based study. The complementary results can be combined in a high performance model, showing the effectiveness of molecular interaction field based approaches to search for novel MMP-13 NZBIs.

The antitumor pharmacological property of flavonoids is correlated with inhibition towards glyoxalase I (GLOI), a critical zinc-enzyme in the methylglyoxal detoxification pathway. In this study, 16 flavonoids were examined, and only baicalein (Ki of 0.183 μM) is identified as a potent in vitro GLOI inhibitor. X-ray crystallographic analysis reveals that baicalein chelates with the catalytic Zn2+ via its characteristic C6/C7 hydroxyl groups. The coordination ability of flavonoids, and therefore their ability to inhibit GLOI, is determined by the Zn2+ coordination geometry, the rigid skeleton of flavonoids and the geometry of the hydrophobic cavity of the GLOI active site. This structural basis could be useful in predicting GLOI inhibition of other natural polyphenols.