CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

Computer-aided drug design to generate a unique antibiotic family.

The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS).

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study.

Objectives: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive.

Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease.

Background: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.

Methods: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.

Results: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration.

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses.

Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aβ-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD.

Furazans in Medicinal Chemistry.

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms.

The Brain Exposure Efficiency (BEE) Score.

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented.

The Blood-Brain Barrier (BBB) Score.

The blood-brain barrier (BBB) protects the brain from the toxic side effects of drugs and exogenous molecules. However, it is crucial that medications developed for neurological disorders cross into the brain in therapeutic concentrations. Understanding the BBB interaction with drug molecules based on physicochemical property space can guide effective and efficient drug design.

Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer.

In a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1-yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERα.

Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators.

In an systematic attempt to develop novel Selective Estrogen Receptor Modulators (SERMs), chiral 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were designed based on an accepted pharmacophore model. Simpler prototypes, viz. racemic 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ols, were first synthesized to develop kinetic resolution to pure enantiomers.

The rise of micropharma.

The drug discovery pipelines of the major pharmaceutical companies have become shockingly depleted, foreshadowing a potential crisis in the ability of Big Pharma to meet the pharmaceutical demands created by the ever-changing spectrum of human disease. However, from this major crisis is emerging a major opportunity, namely micropharma--academia-originated biotech start-up companies that are efficient, innovative, product-focused and small. In this Feature, we discuss a 'new ecosystem' for drug development, with high-risk innovation in micropharma leading to Big Pharma clinical trials; we also identify the 'five golden goals' that micropharma must strive to achieve to attain success.

Cyclopentadiene annulated polycyclic aromatic hydrocarbons: investigations of electron affinities.

The adiabatic electron affinities of cyclopentadiene and 10 associated benzannelated derivatives have been predicted with both density functional and Hartree-Fock theory. These systems can also be regarded as benzenoid polycyclic aromatic hydrocarbons (PAHs) augmented with five-membered rings. Like the PAHs, the electron affinities of the present systems generally increase with the number of rings.