ARTIFICIAL INTELLIGENCE IN PHARMACY DRUG DESIGN

Drug discovery is said to be a multi-dimensional issue in which different properties of drug candidates including efficacy, pharmacokinetics, and safety need to be improved with respect to giving the final drug product. Current advances in fields such as artificial intelligence (AI) systems that refine the design thesis through report investigation, microfluidics-assisted chemical synthesis, and biological testing are now giving a cornerstone for the establishment of greater automation into detail of this process. AI has stimulated computer-aided drug discovery. This could likely speed up time duration for compound discovery and enhancement and authorize more productive hunts of related chemicals. However, such optimization also increases substantial theories, technical, and organizational queries, as well as suspicion about the ongoing boost around them. Machine learning, in particular deep learning, in multiple scientific disciplines, and the development in computing hardware and software, among other factors, continue to power this development worldwide

Nanoparticles in Dentistry ; a review

Nanotechnology finds frequent application in everyday life, particularly in the field of medicine. Due to the capabilities of nanotechnology, examining and manipulating atoms, chemical bonds , and molecules between substances is a relatively straightforward task. When applied in the field of dentistry it is referred to as “nano dentistry”. Nanoparticles which are believed to possess superior efficacy, find significant usage in dentistry, primarily in the prevention and treatment of oral disorders, as well as the maintenance of good oral health and hygiene. Nanoparticles possess distinct characteristics such as their surface to volume ratio, antimicrobial activity, physical, mechanical and biological properties, as well as their particle size. This article provides an overview of the various nanoparticles utilized in dentistry and their respective contributions to the field

A side-effect free method for identifying cancer drug targets

Identifying efective drug targets, with little or no side efects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side efect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identifcation of efective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying efective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as efective candidates for drug development

Mode of presentation rather than the 'weekend effect' is a major determinant of in-hospital mortality

Background The influence of patient demographics and mode of admission on the ‘weekend effect’ remains unclear. This study examins the relationship between day of admission, patient demographics, mode of presentation and survival. Methods Hospital admissions over a three-year period were studied. Patients with an inpatient stay less than 24 h and those who were discharged from the emergency department were excluded. In-hospital mortality was correlated with day of admission, age, gender and mode of presentation in a binary logistical regression analysis. Results There were 448,827 admissions, of which 350,648 (85.7%) occurred during a weekday. 256,777 (62.7%) were emergency presentations, which was closely related to a weekend admission (92.3% vs 57.8%, p < 0.001). There were 8099 deaths of which 6336 (78.2%) related to a weekday admission and 1736 (21.4%) related a weekend admission. Mortality for elective admissions was 78 (0.05%) compared to 8021 (3.12%), p < 0.001 in emergency admissions. Univariable regression analysis revealed a weekend admission (Odds Ratio (OR) 1.68 (95% confidence interval (CI) 1.60–1.78, p < 0.001) and emergency presentation (OR 63.02 (95%CI 50.42–78.77), p < 0.011) were associated with weekend mortality. On multivariable analysis the OR for weekend admission reduced to 1.07 (95%CI 1.01–1.13), p = 0.013 and the OR for emergency presentation increased to 76.68 (95%CI 61.40–96.00), p < 0.001. Conclusion This study highlights that higher weekend mortality rates are a consequence of a lower proportion of elective admissions. Extending the working week to seven days might reduce weekend mortality without reducing the total number of deaths

Silicate weathering and carbon cycle controls on the Oligocene-Miocene transition glaciation

Changes in both silicate weathering rates and organic carbon burial have been proposed as drivers of the transient “Mi-1” glaciation event at the Oligocene-Miocene transition (OMT; ~23 Ma). However detailed geochemical proxy data are required to test these hypotheses. Here we present records of Li/Ca, Mg/Ca, Cd/Ca, U/Ca, δ18O, δ13C, and shell weight in planktonic foraminifera from marine sediments spanning the OMT in the equatorial Atlantic Ocean. Li/Ca values increase by 1 μmol/mol across this interval. We interpret this to indicate a ~20% increase in silicate weathering rates, which would have lowered atmospheric CO2, potentially forcing the Antarctic glaciation circa 23 Ma. δ13C of thermocline dwelling planktonic foraminifera track the global increase in seawater δ13C across the OMT and during the Mi-1 event, hence supporting a hypothesized global increase in organic carbon burial rates. High δ13C previously measured in epipelagic planktonic foraminifera and high Cd/Ca ratios during Mi-1 are interpreted to represent locally enhanced primary productivity, stimulated by increased nutrients supply to surface waters. The fingerprint of high export production and associated organic carbon burial at this site is found in reduced bottom water oxygenation (inferred from high foraminiferal U/Ca), and enhanced respiratory dissolution of carbonates, characterised by reduced foraminiferal shell weight. Replication of our results elsewhere would strengthen the case that weathering-induced CO2 sequestration preconditioned climate for Antarctic ice sheet growth across the OMT and increased burial of organic carbon acted as a feedback that intensified cooling at this time

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706

Influence of the Amazon River on the Nd isotope composition of deep water in the western equatorial Atlantic during the Oligocene–Miocene transition

Dissolved and particulate neodymium (Nd) are mainly supplied to the oceans via rivers, dust, and release from marine sediments along continental margins. This process, together with the short oceanic residence time of Nd, gives rise to pronounced spatial gradients in oceanic 143Nd/144Nd ratios (εNd). However, we do not yet have a good understanding of the extent to which the influence of riverine point-source Nd supply can be distinguished from changes in mixing between different water masses in the marine geological record. This gap in knowledge is important to fill because there is growing awareness that major global climate transitions may be associated not only with changes in large-scale ocean water mass mixing, but also with important changes in continental hydroclimate and weathering. Here we present εNd data for fossilised fish teeth, planktonic foraminifera, and the Fe–Mn oxyhydroxide and detrital fractions of sediments recovered from Ocean Drilling Project (ODP) Site 926 on Ceara Rise, situated approximately 800 km from the mouth of the River Amazon. Our records span the Mi-1 glaciation event during the Oligocene–Miocene transition (OMT; ∼23 Ma). We compare our εNd records with data for ambient deep Atlantic northern and southern component waters to assess the influence of particulate input from the Amazon River on Nd in ancient deep waters at this site. εNd values for all of our fish teeth, foraminifera, and Fe–Mn oxyhydroxide samples are extremely unradiogenic (εNd ≈ −15); much lower than the εNd for deep waters of modern or Oligocene–Miocene age from the North Atlantic (εNd ≈ −10) and South Atlantic (εNd ≈ −8). This finding suggests that partial dissolution of detrital particulate material from the Amazon (εNd ≈ −18) strongly influences the εNd values of deep waters at Ceara Rise across the OMT. We conclude that terrestrially derived inputs of Nd can affect εNd values of deep water many hundreds of kilometres from source. Our results both underscore the need for care in reconstructing changes in large-scale oceanic water-mass mixing using sites proximal to major rivers, and highlight the potential of these marine archives for tracing changes in continental hydroclimate and weathering

Exploring the Trypanosoma brucei Hsp83 Potential as a Target for Structure Guided Drug Design

Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite