Hit diffusion: limitations to drug discovery and structure-based design.

Modern drug discovery employs a 'screening funnel' to pick compounds worthy of advancing to the clinic, a multi-step process linking a series of assays. Molecules which are active in in vitro assays are passed to a cell-based assay, etc. Each pair of assays may be discordant, due to their measuring similar but not identical properties.

Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2.

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.

Cryo-EM as a powerful tool for drug discovery.

The recent revolution in cryo-EM has produced an explosion of structures at near-atomic or better resolution. This has allowed cryo-EM structures to provide visualization of bound small-molecule ligands in the macromolecules, and these new structures have provided unprecedented insights into the molecular mechanisms of complex biochemical processes. They have also had a profound impact on drug discovery, defining the binding modes and mechanisms of action of well-known drugs as well as driving the design and development of new compounds.

Author Correction: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list.

Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency.

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer).

FOCUS--Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists.

Communication of data and ideas within a medicinal chemistry project on a global as well as local level is a crucial aspect in the drug design cycle. Over a time frame of eight years, we built and optimized FOCUS, a platform to produce, visualize, and share information on various aspects of a drug discovery project such as cheminformatics, data analysis, structural information, and design. FOCUS is tightly integrated with internal services that involve-among others-data retrieval systems and in-silico models and provides easy access to automated modeling procedures such as pharmacophore searches, R-group analysis, and similarity searches.

Protein folding, protein homeostasis, and cancer.

Proteins fold into their functional 3-dimensional structures from a linear amino acid sequence. In vitro this process is spontaneous; while in vivo it is orchestrated by a specialized set of proteins, called chaperones. Protein folding is an ongoing cellular process, as cellular proteins constantly undergo synthesis and degradation.

Navigating structure-activity landscapes.

The problem of how to explore structure-activity relationships (SARs) systematically is still largely unsolved in medicinal chemistry. Recently, data analysis tools have been introduced to navigate activity landscapes and to assess SARs on a large scale. Initial investigations reveal a surprising heterogeneity among SARs and shed light on the relationship between 'global' and 'local' SAR features.

Assessing how well a modeling protocol captures a structure-activity landscape.

We introduce the notion of structure-activity landscape index (SALI) curves as a way to assess a model and a modeling protocol, applied to structure-activity relationships. We start from our earlier work [ J. Chem.

Structure--activity landscape index: identifying and quantifying activity cliffs.

A new method for analyzing a structure-activity relationship is proposed. By use of a simple quantitative index, one can readily identify "structure-activity cliffs": pairs of molecules which are most similar but have the largest change in activity. We show how this provides a graphical representation of the entire SAR, in a way that allows the salient features of the SAR to be quickly grasped.

Computer-aided drug design: the next 20 years.

This perspectives article has been taken from a talk the author gave at the symposium in honor of Yvonne C. Martin's retirement, held at the American Chemical Society spring meeting in Chicago on March 25, 2007. The talk was intended as a somewhat lighthearted attempt to gaze into the future; inevitably, in print, things will come across more seriously than was intended.

Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics.

Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated.

Inhibitors of hepatitis C virus NS3.4A protease. Part 3: P2 proline variants.

We recently described the identification of an optimized alpha-ketoamide warhead for our series of HCV NS3.4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P(2).

Inhibitors of hepatitis C virus NS3.4A protease 2. Warhead SAR and optimization.

The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.

Inhibitors of hepatitis C virus NS3.4A protease 1. Non-charged tetrapeptide variants.

Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead.

Pharmacophore discovery--lessons learned.

Pharmacophore discovery is one of the major elements of molecular modeling in the absence of X-ray structural data. While pharmacophores initially made their debut as a means for lead discovery, more recent refinements have brought them into the domain of lead optimization, e.g.

Enhancement of binary QSAR analysis by a GA-based variable selection method.

Binary quantitative structure-activity relationship (QSAR) is an approach for the analysis of high throughput screening (HTS) data by correlating structural properties of compounds with a "binary" expression of biological activity (1 = active and 0 = inactive) and calculating a probability distribution for active and inactive compounds in a training set. Successfully deriving a predictive binary or any QSAR model largely depends on the selection of a preferred set of molecular descriptors that can capture the chemico-biological interaction for a particular biological target. In this study, a genetic algorithm (GA) was applied as a variable selection method in binary QSAR analysis.