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Nonadditivity (NA) in Structure-Activity and Structure-Property Relationship (SAR) data is a rare but very information rich phenomenon. It can indicate conformational flexibility, structural rearrangements, and errors in assay results and structural assignment. While purely ligand-based conformational causes of NA are rather well understood and mundane, other factors are less so and cause surprising NA that has a huge influence on SAR analysis and ML model performance. We here report a systematic analysis across a wide range of properties (20 on-target biological activities and 4 physicochemical ADME-related properties) to understand the frequency of various different phenomena that may lead to NA. A set of novel descriptors were developed to characterize double transformation cycles and identify trends in NA. Double transformation cycles were classified into "surprising" and "mundane" categories, with the majority being classed as mundane. We also examined commonalities among surprising cycles, finding LogP differences to have the most significant impact on NA. A distinct behavior of NA for on-target sets compared to ADME sets was observed. Finally, we show that machine learning models struggle with highly nonadditive data, indicating that a better understanding of NA is an important future research direction., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Novel bacterial topoisomerase inhibitors (NBTIs) make up a promising new class of antibiotics with the potential to combat the growing threat of antimicrobial resistance. Two key challenges in the development of NBTIs have been to obtain broad spectrum activity against multidrug-resistant Gram-negative bacteria and to diminish inhibition of the hERG cardiac ion channel. Here we report the optimization of a series of NBTIs bearing a novel indane DNA intercalating moiety. The addition of a basic, polar side chain connected to the indane by an ether or an N -linked secondary amide linkage together with a lipophilicity-lowering modification of the enzyme binding moiety led to compounds such as 2a and 2g which showed excellent broad spectrum potency and minimal hERG inhibition. Compound 2a demonstrated robust bactericidal in vivo activity in a mouse lung infection model with the strain P. aeruginosa ATCC 27853 which is resistant to several clinically relevant antibiotics. Rodent pharmacokinetic studies with 2a revealed an unusual profile characterized by rapid tissue distribution and a prolonged, flat terminal phase. This profile precluded further development of these compounds as potential new antibiotics., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds 2 and 17a bound to Staphylococcus aureus DNA gyrase-DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the linker and the carboxylate of Asp83. Exploration of the structure-activity relationship within the series led to the identification of lead compound 18c , which showed potent broad-spectrum activity against a panel of MDR Gram-negative bacteria., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

This retrospective, descriptive case-series reviews the clinical presentations and significant laboratory findings of patients diagnosed with and treated for injectional anthrax (IA) since December 2009 at Monklands Hospital in Central Scotland and represents the largest series of IA cases to be described from a single location. Twenty-one patients who fulfilled National Anthrax Control Team standardized case definitions of confirmed, probable or possible IA are reported. All cases survived and none required limb amputation in contrast to an overall mortality of 28% being experienced for this condition in Scotland. We document the spectrum of presentations of soft tissue infection ranging from mild cases which were managed predominantly with oral antibiotics to severe cases with significant oedema, organ failure and coagulopathy. We describe the surgical management, intensive care management and antibiotic management including the first description of daptomycin being used to treat human anthrax. It is noted that some people who had injected heroin infected with Bacillus anthracis did not develop evidence of IA. Also highlighted are biochemical and haematological parameters which proved useful in identifying deteriorating patients who required greater levels of support and surgical debridement.

Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.

In a recent study, we presented a novel quantitative-structure-activity-relationship (QSAR) approach, combining R-group signatures and nonlinear support-vector-machines (SVM), to build interpretable local models for congeneric compound sets. Here, we outline further refinements in the fingerprint scheme for the purpose of analyzing and visualizing structure-activity relationships (SAR). The concept of distance encoded R-group signature descriptors is introduced, and we explore the influence of different signature encoding schemes on both interpretability and predictive power of the SVM models using ten public data sets. The R-group and atomic gradients provide a way to interpret SVM models and enable detailed analysis of structure-activity relationships within substituent groups. We discuss applications of the method and show how it can be used to analyze nonadditive SAR and provide intuitive and powerful SAR visualizations.

The productivity challenge facing the pharmaceutical industry is well documented. Strategies to improve productivity have mainly focused on enhancing efficiency, such as the application of Lean Six Sigma process improvement methods and the introduction of modeling and simulation in place of 'wet' experiments. While these strategies have their benefits, the real challenge is to improve effectiveness by reducing clinical failure rates. We advocate redesigning the screening cascade to identify and optimize novel compounds with improved efficacy against disease, not just with improved potency against the target. There should be greater use of disease-relevant phenotypic screens in conjunction with target-based assays to drive medicinal chemistry optimization. An opportunistic approach to polypharmacology is recommended. There should also be more emphasis on optimization of the molecular mechanism of action incorporating understanding of binding kinetics, consideration of covalent drug strategies and targeting allosteric modulators.

The 'quality' of small-molecule drug candidates, encompassing aspects including their potency, selectivity and ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics, is a key factor influencing the chances of success in clinical trials. Importantly, such characteristics are under the control of chemists during the identification and optimization of lead compounds. Here, we discuss the application of computational methods, particularly quantitative structure-activity relationships (QSARs), in guiding the selection of higher-quality drug candidates, as well as cultural factors that may have affected their use and impact.

Many commonly prescribed drugs can interact with warfarin and prolong bleeding time beyond therapeutic limits. We report a patient who developed a rectus sheath haematoma following inadvertent over anticoagulation. Despite conservative management, the patient went on to develop large bowel obstruction from the expanding haematoma and operative intervention became necessary.

Today's drug designer has access to vast quantities of data and an impressive array of sophisticated computational methods. At the same time, there is increasing pressure on the pharmaceutical industry to improve its productivity and reduce candidate drug attrition. We set out to develop a highly integrated suite of design and data analysis tools underpinned by the best predictive chemistry methods and models, with the aim of enabling multi-disciplinary compound design teams to make better informed design decisions. In this article we address the challenges of developing a powerful, flexible and user-friendly toolkit, and of maximising its exploitation by the design community. We describe the impact the toolkit has had on drug discovery projects and give our perspective on the future direction of this activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We present an automated QSAR procedure that is used in AstraZeneca's AutoQSAR system. The approach involves automatically selecting the most predictive models from pools of both global and local models. The effectiveness of this QSAR modelling strategy is demonstrated with a retrospective study that uses a diverse selection of 9 early stage AstraZeneca drug discovery projects and 3 physicochemical endpoints: LogD; solubility and human plasma protein binding. We show that the strategy makes a statistically significant improvement to the accuracy of predictions when compared to an updating global strategy, and that the systematic biases inherent in the global model predictions are almost completely removed. This improvement is attributed to the model selection aspect of the strategy., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl] propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human CCR5 chemokine receptor with good oral pharmacokinetic properties.

SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.

The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and alpha,beta-unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of (+)-virgatusin (ent-1). [reaction: see text]

Investigation of weak screening hits led to the identification of N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides and N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N'-benzylureas as potent, selective ligands for the human CCR5 chemokine receptor.

SAR studies led to the identification of 4-(3-benzoylamino-6-methyl-anilino)quinazolines as potent and selective inhibitors of p38 MAP kinase. Further optimisation led to the identification of a series of 4-(3-benzoylamino-6-methyl-anilino)pyrimidines as potent inhibitors of the p38 MAP kinase signalling pathway in vitro and in vivo.

This report describes the successful development of a transplantation model in which we engrafted adult murine bone marrow hematopoietic cells in congenic day-old murine pups. Newborn animals conditioned with high doses (> or = 7.0 Gy) of total-body irradiation (TBI) demonstrated severe growth retardation and untoward effects on the developing central nervous system. Newborn pups conditioned with a sublethal dose (5.0 Gy) of TBI, however, achieved normal growth and development up to 6 months posttransplantation, and donor type hematopoietic cell reconstitution exceeded 50% in these animals. A second conditioning regimen, comprising one or two doses of busulfan (15 mg/kg) administered intrapartum, resulted in significant myelosuppression in untransplanted newborn pups. This second regimen was associated, however, with engraftment and full multilineage reconstitution of the conditioned newborn recipient animals with adult bone marrow cells, and the engrafted pups grew and developed without apparent defect. A third conditioning regimen combining a single dose of busulfan with sublethal TBI also permitted engraftment and full multilineage reconstitution of the recipient animals. Thus, successful transplantation of hematopoietic cells into newborn recipient mice may be achieved without significant morbidity if a specific conditioning regimen is employed.

The functional activity of the sphincter of Oddi complex has been examined by ceruletide manometry in patients undergoing cholecystectomy with a normal peroperative cholangiogram. In Group I (n = 14), which included patients with previous acute cholecystitis/biliary colic, the sphincter activity appeared to be normal and responded to intravenous ceruletide by a marked relaxation with a significant fall in both the infusion and postinfusion pressures. In patients undergoing cholecystectomy for gallstone-associated pancreatitis (n = 8), the sphincter exhibited manometric features of hypotonia with low infusion and postinfusion pressures which were not significantly altered by intravenous ceruletide.

In a prospective study of 60 patients undergoing investigation for possible exocrine pancreatic disease the fluorescein-dilaurate test was compared with the secretin-cholecystokinin (CCK) test. Forty one patients had a normal response to secretin-CCK, 14 patients had abnormal responses and in five patients the results were equivocal. Taking the secretin-CCK test as the diagnostic criterion, the fluorescein-dilaurate test had a sensitivity of 100% and a negative predictive value of 100%. There was a 54% false-positive rate. The fluorescein-dilaurate test is easy to perform and is a useful screening test for pancreatic exocrine insufficiency.

In the fluorescein dilaurate test fluorescein dilaurate is cleaved by the pancreas specific cholesterol ester hydrolase activity and the liberated fluorescein is absorbed and excreted in the urine. Fluorescein recovery is a reflection of exocrine pancreatic function. The test was evaluated in 14 patients with cystic fibrosis and 16 healthy volunteers. The test was well tolerated by patients, was easy to perform, and gave significantly lower values in the patients suffering from cystic fibrosis. The result of the pancreolauryl test was also correlated with the result of the faecal chymotrypsin test in 11 of the patients suffering from cystic fibrosis. A positive correlation was found between the two test results. The test is a practical and reliable index of pancreatic exocrine function and may have a useful role as a screening procedure.

Subtotal pancreatectomy was performed in the male Wistar rat in order to obtain a model for the study of pancreatic regeneration. Adherence to previously published techniques caused an unacceptably high operative mortality due to duodenal necrosis. The operation was modified after a detailed study of the duodenal vasculature was performed and this modification together with meticulous haemostasis enabled the procedure to be performed with an acceptable operative mortality. The procedure ensured that between 73 and 83% of the total pancreatic mass was removed.

50 below-knee amputations were carried out in 45 patients (25 men and 20 women), mean (SD) age 73 (10.5) years. The mean survival time was 22(16) months after the operation. In each patient the healing potential of a below-knee amputation was determined preoperatively by segmental pressure studies and thermographic delineation of skin perfusion. 33 of the stumps healed by first intention, in 14 healing was delayed but occurred without the need for further surgery, and 3 stumps healed after local wedge excision. The initial mobilisation rate was 90%. Thus, there are no grounds for carrying out an initial above-knee amputation to save the patient a further operation.

Results of lower limb amputation in the Tayside Region in the years 1981-1985 have been analysed. Three-hundred and twenty-four amputations were performed on three-hundred and eight patients. Two-hundred and thirty-six amputations were attempted at the below-knee level. Only 19 required proximal revision. Prior to amputation, all patients should have a detailed vascular assessment, and the operation should be performed by experienced amputation surgeons using meticulous technique.

One hundred patients with phlebographically proved acute deep vein thrombosis of the legs were prospectively randomised into two treatment groups to compare the safety and efficacy of subcutaneous calcium heparin versus intravenous sodium heparin administered by constant infusion pump. The dose of heparin was determined by daily measurement of the kaolin cephalin clotting time. Treatment was maintained for up to 14 days, after which phlebography was repeated. Of 49 patients who received subcutaneous calcium heparin, two showed an increase in thrombus size, while eight showed complete lysis. In the 47 patients who received intravenous sodium heparin thrombus increased in size in 13 while only one showed evidence of complete lysis. These differences were significant. There were no significant differences between the two groups in the incidence of serious complications, although almost half of those receiving intravenous heparin had some minor problem with the constant infusion pump and just over half of those receiving subcutaneous heparin had some bruising at the injection site. This study showed that subcutaneous calcium heparin was more effective in helping lyse existing thrombus and preventing its propagation than intravenous sodium heparin.

This author places greatest emphasis on blocking the major avenue of saliva-borne disease distribution, which he says can be done effectively by the use of boiling water in dishwashing. He figures that the influenza-pneumonia mortality in institutions using boiling water was only half that of similar institutions with handwashed dishes.

Risk of infecting the hand through careless dishwashing, mess-kit washing being the method considered, has already been discussed by this author. Here he follows up field observation with laboratory tests. He oxonerates home dishwashing and states that it is not a major route of hand infection.

War camp statistics are surprising in the evidence they afford that the camps were nurseries of carrier-borne infections and their complications. This author emphasizes the need of attention to the carrier, who is a very important health risk. Prevention here demands sanitary attention in inter-epidemic times as well as during the run of epidemics.

Colonel Cumming extends the trail he blazed in the matter of in-sanitary dishwashing. He finds in institutions that wash by hand in lukewarm water that there was three times the incidence of influenza-pneumonia that there was in institutions with steam dishwashing. His conclusions are based on an institution population of 252,186.