From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Comparison of structure- and ligand-based scoring functions for deep generative models: a GPCR case study.

Deep generative models have shown the ability to devise both valid and novel chemistry, which could significantly accelerate the identification of bioactive compounds. Many current models, however, use molecular descriptors or ligand-based predictive methods to guide molecule generation towards a desirable property space. This restricts their application to relatively data-rich targets, neglecting those where little data is available to sufficiently train a predictor. Moreover, ligand-based approaches often bias molecule generation towards previously established chemical space, thereby limiting their ability to identify truly novel chemotypes. In this work, we assess the ability of using molecular docking via Glide-a structure-based approach-as a scoring function to guide the deep generative model REINVENT and compare model performance and behaviour to a ligand-based scoring function. Additionally, we modify the previously published MOSES benchmarking dataset to remove any induced bias towards non-protonatable groups. We also propose a new metric to measure dataset diversity, which is less confounded by the distribution of heavy atom count than the commonly used internal diversity metric. With respect to the main findings, we found that when optimizing the docking score against DRD2, the model improves predicted ligand affinity beyond that of known DRD2 active molecules. In addition, generated molecules occupy complementary chemical and physicochemical space compared to the ligand-based approach, and novel physicochemical space compared to known DRD2 active molecules. Furthermore, the structure-based approach learns to generate molecules that satisfy crucial residue interactions, which is information only available when taking protein structure into account. Overall, this work demonstrates the advantage of using molecular docking to guide de novo molecule generation over ligand-based predictors with respect to predicted affinity, novelty, and the ability to identify key interactions between ligand and protein target. Practically, this approach has applications in early hit generation campaigns to enrich a virtual library towards a particular target, and also in novelty-focused projects, where de novo molecule generation either has no prior ligand knowledge available or should not be biased by it.

Methodologies for the Examination of Water in GPCRs.

The following chapter examines some of the current "state-of-the-art" tools for predicting, scoring, and examining explicit water molecules in proteins and protein/ligand complexes, highlighting some of the ways information can be readily examined in a manner that is useful in a drug discovery process.

TAK1 inhibition in the DFG-out conformation.

The first example of an inhibitor of the kinase TAK1 that binds in the DFG-out conformation is disclosed. These preliminary studies used kinase-targeted screening and structure-based drug design to create a molecule with dual pharmacological inhibition of p38 and TAK1 that demonstrated significant activity in a cell-based, anti-inflammatory assay.

Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease.

This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.

Effect of suture size and type on bone cutout in transosseous tendon repairs.

PURPOSE: We compared bone cutout of polyester and polyblend suture in 2 suture sizes with static and cyclic loading in a Sawbone model (Pacific Research Laboratories, Vashon, WA). METHODS: Polyester and polyblend sutures in both No. 2 and No. 5 sizes were placed through transosseous tunnels in closed-cell polyurethane foam and tied over the bar of an electromechanical load frame at a fixed height. Seven sutures in each group were pulled at a rate of 1 mm/s until bone cutout occurred. Another set of 28 sutures were cyclically loaded at increasing loads until failure. RESULTS: With static and cyclic loads, No. 5 polyester suture (Ethibond; Ethicon, Somerville, NJ) and No. 5 polyblend suture (FiberWire; Arthrex, Naples, FL) had a higher cutout load than the No. 2 sutures (P < .001). No. 2 polyblend suture had a higher static failure load than No. 2 polyester suture (P = .02). With cyclic loading, No. 2 polyblend suture had a higher load to cutout than No. 2 polyester suture (P = .01), and No. 5 polyblend suture had a higher load to cutout than No. 5 polyester suture (P = .003). CONCLUSIONS: No. 2 sutures showed bone cutout at lower forces under static and cyclic loading as compared with No. 5 sutures in this Sawbone model, and no decrease in performance with regard to bone cutout was noted with polyblend as compared with polyester. CLINICAL RELEVANCE: No. 5 polyester or polyblend suture may be preferable to No. 2 suture to avoid bone cutout in tendon-to-bone repair, and No. 5 polyblend may be preferable to No. 5 polyester to avoid bone cutout.

Elongation behavior of calcaneofibular and cervical ligaments in a closed kinetic chain: pathomechanics of lateral hindfoot instability.

Numerous reconstructive procedures are performed to correct both ankle and subtalar instability after trauma although the precise pathology which results in this chronic instability and pain is not yet known. This study examined the role of the calcaneofibular (CLFL) and cervical ligaments (CRVL) during physiologic loading and demonstrated the effect of CLFL deficiency on the CRVL. Talar and subtalar tilt as well as inversion range of motion before and after CLFL sectioning were studied. Eleven osteoligamentous fresh frozen cadaver legs were used in which each foot was taken through six positions: neutral, 35 degrees plantarflexion, dorsiflexion, inversion, plantarflexion-inversion, and dorsiflexion-inversion. The CLFL and CRVL stretched the greatest in dorsiflexion-inversion. The most interesting finding was that the CRVL was elongated relative to neutral in all other test positions of the foot. However, the CLFL was shortened relative to neutral in plantarflexion and plantarflexion-inversion. In the CLFL deficient state, CRVL ratios demonstrated significant increases in length of the CRVL. Talar tilt increased on average more than 9 degrees with CLFL deficiency (p < 0.008) while subtalar tilt did not change significantly. The maximum tibiocalcaneal angle, recorded for dorsiflexion-inversion, increased more than 5 degrees after sectioning the CLFL (p < 0.05).