The Front Cover summarizes the computational pipeline which characterises HT-SuMD, a computational protocol exploiting supervised molecular dynamics simulations to perform the posing of a small fragment library. In this study, HT-SuMD accuracy in anticipating the fragment-bound conformations has been validated using a dataset of 23 noncovalent complexes, recently identified through an X-ray crystallographic fragment screening against the SARS-CoV-2 main protease(M^pro). More information can be found in the Communication by Mattia Sturlese, Stefano Moro et al.

Titan of the toolkit: The Asinger multicomponent reaction can play an important role in drug design and discovery due to the diversity and complexity that offers. Here, we present the scope and limitations of the reaction, its orthogonal combination with classic or other MCRs and the applications in drug discovery. We believe that Asinger reaction will find its position in today's sustainable chemistry.

Strategies for downregulating the androgen receptor (AR) have attracted significant attention. Stabilizers of G-quadruplexes, inhibitors of RORγ, and inhibitors of BET-BRD downregulate AR mRNA levels. Antisense oligonucleotides designed for AR splice variants premRNA were shown to inhibit the expression of AR splice variants, while selective AR degraders like proteolysis targeting chimeras (PROTACs) can induce AR protein degradation.

Metal ions play fundamental structural, functional, and regulatory roles in biomolecules. In this compendium, we exemplify how all-atom simulations have contributed to unravel the mechanistic facets underlying catalysis, transport, and inhibition of metal-binding proteins. Harnessing this knowledge is essential to successfully develop selective small-molecules inhibitors to improve human health condition.

Heterocyclic compounds constitute a unique class of organic compounds endowed with a wide range of synthetic and pharmaceutical applications. Pyrimidinones and their fused analogues have received focused attention in this regard, partly due to their mimicry of nucleobases which consequently forges their interesting medicinal properties. This minireview presents a compendium of recent developments (2017–2020) focused on the synthesis and biological activities of fused pyrimidinones to help update medicinal chemists on the therapeutic relevance of fused pyrimidinones and the molecular architecture of clinic-worthy drug candidates.

Accuracy in binding:This study assessed the geometric accuracy with which HT-SuMD protocol can reproduce the experimentally solved binding modes for a set of 23 X-Ray crystallographic fragment-receptor complexes of the SARS-CoV-2 M^pro. Differently from the original publication, the integration of an MD-based refinement step, with the RMSD_SuMD implemented as a metric characterizing the poses structural stability, has allowed to improve the protocol's ability in prioritizing only the most accurate binding predictions.

Ring binder: Co-crystal structures of human PHD2 with Molidustat and a related inhibitor provide insight into their mode of inhibition. The pyrazolone-pyrimidine rings of Molidustat chelate the active-site metal ion, and its triazole ring makes a π-π-stacking interaction with Tyr303. The results reveal altered conformations of PHD2 residues, including Tyr303 and Tyr310 on binding of Fe-chelating PHD inhibitors.

False positive results are unfortunately common in medicinal-chemistry workflows. The unsuccessful parts of the stories are only rarely shared. In our decomposition study on an antimalarial 2-aminothiazole, we observed degradation in DMSO. We successfully isolated by SFC and elucidated the structure of decomposition products contributing to the activities against the Plasmodium falciparum NF54 cell line and the target enzyme IspE.

Fighting protozoan parasites: Herein, we present a first molecular model (experimentally corroborated) for the adenylyl cyclase of Giardia lamblia, an enzyme involved in growth and differentiation of this parasite. In addition, we also report the discovery of a novel inhibitor, an N-(piperidin-4-yl)-1H-pyrrole-2-carboxamide derivative, which becomes an interesting starting structure for the development of new inhibitors for this enzyme.

A comprehensive study of hymeglusin is described. We identified that hymeglusin shows a circumventing effect against β-lactam drug resistance in methicillin-resistant Staphylococcus aureus. Our concise total synthetic route contributed to the first total synthesis of the congener, fusarilactone A and synthetic derivatives allowed us to clarify SAR. The enzyme inhibition assay and site-directed mutagenesis studies suggested the target protein.

Lack of progress in the development and clinical approval of new therapeutics for antibiotic-resistant infections is concerning from a public health perspective. We report that the addition of a copper-binding motif promotes synergistic activity of synthetic antimicrobial peptides against methicillin-resistant staphylococcus aureus (MRSA) and explore the underlying mechanism of action which involves co-localization of both peptides within the cell, DNA damage, lipid oxidation, and an upregulation of reactive oxygen species (ROS).

Xanthenylacetic acid (XAA) derivatives effectively inhibit hepatocellular carcinoma (HCC) cell growth by targeting lysophosphatidic acid receptor 6 (LPAR6) in an enantioselective manner. Our results bring original insights on the characteristics of the LPAR6 binding site and on the chemico-physical properties of the novel LPAR6 antagonists. This will drive the design of more efficient LPAR6 antagonists expanding the therapeutic tools against HCC.

Novel chiral ionone alkaloid derivatives were synthesized, and compound 11 g with higher antichemotactic migration activity than the lead compound was screened. Compound 11 g exerted inhibitory effects on the adhesion, migration and invasion of MDA-MB-231 cells. The mechanisms for the antitumor metastatic effects of 11 g might be that it inhibited HIF-1α expression to down regulate the secretion of VEGF and the phosphorylation of VEGFR2, and then suppressed the downstream pathways, including Akt1/mTOR/p70S6K and Akt2/PKCζ/integrin β1.

The diversity of natural products was explored to identify small-molecule based modulators or structural-correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Through metastable-reporter based primary screen and a secondary screen with disease-specific pathogenic protein, pharmacological chaperone activity of flavonoid glycoside (C-10, chrysoeriol-7-O-β-D-glucopyranoside) is demonstrated. Data suggests that C-10 stabilizes metastable protein, remodels the oligomers, inhibits protein aggregation and mitigates aggregation-associated cytotoxic effects.