Mathematical modeling for prediction of physicochemical characteristics of cardiovascular drugs via modified reverse degree topological indices.

Global health concerns persist due to the multifaceted nature of heart diseases, which include lifestyle choices, genetic predispositions, and emerging post-COVID complications like myocarditis and pericarditis. This broadens the spectrum of cardiovascular ailments to encompass conditions such as coronary artery disease, heart failure, arrhythmias, and valvular disorders. Timely interventions, including lifestyle modifications and regular medications such as antiplatelets, beta-blockers, angiotensin-converting enzyme inhibitors, antiarrhythmics, and vasodilators, are pivotal in managing these conditions. In drug development, topological indices play a critical role, offering cost-effective computational and predictive tools. This study explores modified reverse degree topological indices, highlighting their adjustable parameters that actively shape the degree sequences of molecular drugs. This feature makes the approach suitable for datasets with unique physicochemical properties, distinguishing it from traditional methods that rely on fixed degree approaches. In our investigation, we examine a dataset of 30 drug compounds, including sotagliflozin, dapagliflozin, dobutamine, etc., which are used in the treatment of cardiovascular diseases. Through the structural analysis, we utilize modified reverse degree indices to develop quantitative structure-property relationship (QSPR) models, aiming to unveil essential understandings of their characteristics for drug development. Furthermore, we compare our QSPR models against the degree-based models, clearly demonstrating the superior effectiveness inherent in our proposed method.

The U.S. FDA approved cardiovascular drugs from 2011 to 2023: A medicinal chemistry perspective.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. A total of 28 new molecular entities (NMEs) were approved by the U.S. Food and Drug Administration (FDA) for the treatment of cardiovascular diseases from 2011 to 2023. Approximately 25 % of the medications were sanctioned for the management of diverse vascular disorders. The other major therapeutic areas of focus included antilipemic agents (15 %), blood pressure disease (11 %), heart failure, hyperkalemia, and cardiomyopathy (7-8% each). Among all the approved drugs, there are a total of 22 new chemical entities (NCEs), including inhibitors, agonists, polymers, and inorganic compounds. In addition to NCEs, 6 biological agents (BLAs), including monoclonal antibodies, small interfering RNAs (siRNAs), and antisense oligonucleotides, have also obtained approval for the treatment of cardiovascular diseases. From this perspective, approved NCEs are itemized and discussed based on their disease, targets, chemical classes, major drug metabolites, and biochemical and pharmacological properties. Systematic analysis has been conducted to examine the binding modes of these approved drugs with their targets using cocrystal structure information or docking studies to provide valuable insights for designing next-generation agents. Furthermore, the synthetic approaches employed in the creation of these drug molecules have been emphasized, aiming to inspire the development of novel, efficient, and applicable synthetic methodologies. Generally, the primary objective of this review is to provide a comprehensive examination of the clinical applications, pharmacology, binding modes, and synthetic methodologies employed in small-molecule drugs approved for treating CVD. This will facilitate the development of more potent and innovative therapeutics for effectively managing cardiovascular diseases.

Identification of Riluzole derivatives as novel calmodulin inhibitors with neuroprotective activity by a joint synthesis, biosensor, and computational guided strategy.

The development of new molecules for the treatment of calmodulin related cardiovascular or neurodegenerative diseases is an interesting goal. In this work, we introduce a novel strategy with four main steps: (1) chemical synthesis of target molecules, (2) Förster Resonance Energy Transfer (FRET) biosensor development and in vitro biological assay of new derivatives, (3) Cheminformatics models development and in vivo activity prediction, and (4) Docking studies. This strategy is illustrated with a case study. Firstly, a series of 4-substituted Riluzole derivatives 1-3 were synthetized through a strategy that involves the construction of the 4-bromoriluzole framework and its further functionalization via palladium catalysis or organolithium chemistry. Next, a FRET biosensor for monitoring Ca2+-dependent CaM-ligands interactions has been developed and used for the in vitro assay of Riluzole derivatives. In particular, the best inhibition (80%) was observed for 4-methoxyphenylriluzole 2b. Besides, we trained and validated a new Networks Invariant, Information Fusion, Perturbation Theory, and Machine Learning (NIFPTML) model for predicting probability profiles of in vivo biological activity parameters in different regions of the brain. Next, we used this model to predict the in vivo activity of the compounds experimentally studied in vitro. Last, docking study conducted on Riluzole and its derivatives has provided valuable insights into their binding conformations with the target protein, involving calmodulin and the SK4 channel. This new combined strategy may be useful to reduce assay costs (animals, materials, time, and human resources) in the drug discovery process of calmodulin inhibitors.

Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.

The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.

Computational study of therapeutic potential of phosphorene as a nano-carrier for drug delivery of nebivolol for the prohibition of cardiovascular diseases: a DFT study.

Density functional theory (DFT) calculations were utilized to assess the drug delivery efficiency of phosphorene carrier for nebivolol drug to treat cardiovascular diseases. The optimized structures, excited state, and electronic properties of nebivolol, phosphorene, and nebivolol-phosphorene (nebivolol-PH) complex were considered to determine the drug delivery ability of phosphorene at the target site. The increased dipole moment (6.08 D) results in the higher solubility of the complex in polar solvents (water). Weak interactive forces between nebivolol and phosphorene were demonstrated by the non-covalent interaction (NCI) plot that facilitated the offloading of nebivolol at the targeted area. The analysis of frontier molecular orbitals (FMOs) revealed that during excitation, the charge was transferred from nebivolol as a higher occupied molecular orbital (HOMO) to phosphorene as a lower unoccupied molecular orbital (LUMO). Thus, the charge-transfer process was further studied by charge decomposition analysis (CDA). The calculated results at the excited state for the nebivolol-PH complex exhibited that the maximum wavelength (λmax) was red-shifted by 6 nm in the gas phase. The electron-hole theory and photoinduced electron transfer (PET) processes were carried out for the exploration of different excited states of the complex. Additionally, phosphorene with + 1 and - 1 charge states indicated the minor structural changes and provide the stable nebivolol-PH complex. This theoretical study also investigated that phosphorene can be exploited as an effective carrier for the delivery of a therapeutic agent as nebivolol to treat cardiovascular diseases. This work will also encourage the researchers to investigate the other 2D nanoparticles as a nano-drug delivery system (NDDS).

Characterization and bioactivities of phospholipids from squid viscera and gonads using ultra-performance liquid chromatography-Q-exactive orbitrap/mass spectrometry-based lipidomics and zebrafish models.

There has been great interest in phospholipids (PLs) from marine by-products due to their long-chain polyunsaturated fatty acids with unique health and functional properties. Here, marine PLs from squid viscera and gonads were comprehensively characterized and compared by UPLC-Q-Exactive Orbitrap/MS-based lipidomics analysis. A total of thirteen phospholipid classes including 1223 molecular species were identified and quantified in both resources. PC, PE and SM were further isolated from the total PLs of squid viscera and gonads, respectively. All isolated squid PL components were first evaluated for anti-inflammatory, antioxidant and cardiovascular effects using in vivo zebrafish models. Our results showed the diversity, content and physiological functions of PLs from squid by-products, which provided a basis for their future application in the nutritional and pharmaceutical industry.

Myxadazoles, Myxobacterium-Derived Isoxazole-Benzimidazole Hybrids with Cardiovascular Activities.

There is a continuous need for novel microbial natural products to fill the drying-up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N-ribityl 5,6-dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non-canonical PKS/NRPS gene cluster, whereas the origin of N-ribityl 5,6-dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C-N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.

Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development.

Drug development in cardiovascular disease is stagnating, with lack of efficacy and adverse effects being barriers to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization, with genetic support for causation increasing the probability of a clinical trial succeeding. Mendelian randomization applied to quantitative traits can identify risk factors for disease that are both causal and amenable to therapeutic modification. However, important differences exist between genetic investigations of a biomarker (such as HDL cholesterol) and a drug target aimed at modifying the same biomarker of interest (such as cholesteryl ester transfer protein), with implications for the methodology, interpretation and application of Mendelian randomization to drug development. Differences include the comparative nature of the genetic architecture - that is, biomarkers are typically polygenic, whereas protein drug targets are influenced by either cis-acting or trans-acting genetic variants - and the potential for drug targets to show disease associations that might differ from those of the biomarker that they are intended to modify (target-mediated pleiotropy). In this Review, we compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits. We explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.

Human iPSC modeling of heart disease for drug development.

Human induced pluripotent stem cells (hiPSCs) have emerged as a promising platform for pharmacogenomics and drug development. In cardiology, they make it possible to produce unlimited numbers of patient-specific human cells that reproduce hallmark features of heart disease in the culture dish. Their potential applications include the discovery of mechanism-specific therapeutics, the evaluation of safety and efficacy in a human context before a drug candidate reaches patients, and the stratification of patients for clinical trials. Although this new technology has the potential to revolutionize drug discovery, translational hurdles have hindered its widespread adoption for pharmaceutical development. Here we discuss recent progress in overcoming these hurdles that should facilitate the use of hiPSCs to develop new medicines and individualize therapies for heart disease.

Separation, identification and cardiovascular activities of phospholipid classes from the head of Penaeus vannamei by lipidomics and zebrafish models.

Phospholipids not only have high nutritional value, but also have a positive effect on cardiovascular disease, cancer and nervous system diseases. However, the activity of individual phospholipid classes of shrimp phospholipids is rarely studied. This paper researched phospholipids in the by-products of Penaeus vannamei processing. The phospholipid classes of the head from P. vannamei (PV) were separated by column chromatography, analyzed with UHPLC-Q-Exactive HF/MS, and quantified using ammonium ferrothiocyarate spectrophometry. In addition, their cardiovascular activities in zebrafish models were evaluated. A total of 5 phospholipid classes were obtained, including PV-PC, PV-PE, PV-PI, PV-PS and PV-SM, and identified as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS) and sphingomyelin (SM), respectively. In the phospholipid profiling analysis, PV-PC (308 molecules) had the highest proportion with 85.24%, followed by PV-PE (139 types) with 9.32%, PV-SM (41 structures) with 4.75%, PV-PS (24 types) with 0.16%, and PV-PI (6 molecules) with 0.03%. In the quantitative analysis, the content of PV was 45.7%, and the purity of phospholipid classes was 75.5-88.1%. In the cardiovascular activity assays, the effects of different phospholipid classes were different. For example, PV-PC groups had strong angiogenesis activity, but PV-PE groups showed the opposite property. Our comprehensive profiling analysis and in vivo bioactivity evaluation of phospholipids from the head of P. vannamei can provide evidence for their targeted applications in the future.

Plant Terpenes on Treating Cardiovascular and Metabolic Disease: A Review.

The use of medicinal plants as a therapy alternative is old as human existence itself. Nowadays, the search for effective molecules for chronic diseases treatments has increased. The cardiometabolic disorders still the main cause of death worldwide and plants may offer potential pharmacological innovative approaches to treat and prevent diseases. In the range of plant molecules are inserted the terpenes, which constituent essential elements with several pharmacological characteristics and applications, including cardiovascular and metabolic properties. Thus, the aim of the present review is to update the terpenes use on chronic disorders such as obesity, diabetes, hypertension and vascular conditions. The review includes a brief terpenes description based on the scientific literature in addition to data collected from secondary sources such as books and conference proceedings. We concluded that terpenes could act as adjuvant or main alternative treatment (when started earlier) to improve cardiometabolic diseases, contributing to reduce side effects of conventional drugs, in addition to preserving ethnopharmacological knowledge.

In Vitro Demonstration of Drug-Reagent Interactions Among Commonly Used Parenteral Drugs in Cardiology.

BACKGROUND: Drug-drug interactions are undesirable, as they reduce drug bioavailability. Drug-reagent interactions in biochemical tests may directly affect the accuracy of test results. OBJECTIVE: The aim of the present study was to investigate the impact of drug-reagent interactions of drugs used in cardiology on different cardiac markers (troponin I, Nt-proBNP, CK-MB mass, CK, AST, and LDH) and the D-dimer test. METHODS: Eleven drugs (enoxaparin, tirofiban hydrochloride monohydrate, diltiazem, glyceryl trinitrate, metoprolol, epinephrine, heparin sodium, atropine sodium, furosemide, norepinephrine tartrate, and amiodarone HCl) were tested in an interference study. The interference protocol was applied to the control material of troponin I, CK-MB mass, Nt-proBNP, CK, AST, LDH tests with 11 different drugs and performed with analyzers. Cardiac Markers Plus Control (Bio-Rad, Irvine, CA, USA; Lot: 23662) materials were used to assess the impact of drug-reagent interactions on the accuracy of tests of cardiac markers based on immunoassay methods. The bias rate, defined as the extent of deviation from the target value (bias %), in the interference study was calculated in each test. RESULTS: For all 11 drugs, positive interference in the range of 43.58% to 130.06% occurred in the CK-MB mass test, whereas positive interference in the range of 11.98% to 107.44% occurred in the troponin I test. All the drugs, except enoxaparin sodium, led to negative interference in the range of - 84.21 to -29.6% in the Nt-proBNP test. In the D-dimer test, amiodarone HCl and diltiazem caused interference (122.87% and 28.08%, respectively). The percentage of interference caused by the other drugs ranged from -1.27% to 11.44%. Minimal deviations in the target values (between -3.31% and 3.86%) were observed in the CK, AST, and LDH tests measured using spectrophotometric methods. CONCLUSION: Parenteral drugs used in cardiology can significantly interfere with troponin I, CK-MB mass, Nt-proBNP, and D-dimer tests in the analytical phase because of drug-reagent interactions. Minimal deviations in the CK, AST, and LDH tests were observed using spectrophotometric methods. Thus, changes in test results may be due to drug interference rather than the treatment itself. Clinicians should consider the possibility of drug interference in cases of doubtful cardiac test results that do not comply with the diagnosis.

Importance of scientific collaboration in contemporary drug discovery and development: a detailed network analysis.

BACKGROUND: Growing evidence shows that scientific collaboration plays a crucial role in transformative innovation in the life sciences. For example, contemporary drug discovery and development reflects the work of teams of individuals from academic centers, the pharmaceutical industry, the regulatory science community, health care providers, and patients. However, public understanding of how collaborations between academia and industry catalyze novel target identification and first-in-class drug discovery is limited. RESULTS: We perform a comprehensive network analysis on a large scientific corpus of collaboration and citations (97,688 papers with 1,862,500 citations from 170 million scientific records) to quantify the success trajectory of innovative drug development. By focusing on four types of cardiovascular drugs, we demonstrate how knowledge flows between institutions to highlight the underlying contributions of many different institutions in the development of a new drug. We highlight how such network analysis could help to increase industrial and governmental support, and improve the efficiency or accelerate decision-making in drug discovery and development. CONCLUSION: We demonstrate that network analysis of large public databases can identify and quantify investigator and institutional relationships in drug discovery and development. If broadly applied, this type of network analysis may help to enhance public understanding of and support for biomedical research, and could identify factors that facilitate decision-making in first-in-class drug discovery among academia, the pharmaceutical industry, and healthcare systems.

Current Research Landscape of Marine-Derived Anti-Atherosclerotic Substances.

Atherosclerosis is a chronic disease characterized by lipid accumulation and chronic inflammation of the arterial wall, which is the pathological basis for coronary heart disease, cerebrovascular disease and thromboembolic disease. Currently, there is a lack of low-cost therapeutic agents that effectively slow the progression of atherosclerosis. Therefore, the development of new drugs is urgently needed. The research and development of marine-derived drugs have gained increasing interest from researchers across the world. Many marine organisms provide a rich material basis for the development of atherosclerotic drugs. This review focuses on the latest technological advances in the structures and mechanisms of action of marine-derived anti-atherosclerotic substances and the challenges of the application of these substances including marine polysaccharides, proteins and peptides, polyunsaturated fatty acids and small molecule compounds. Here, we describe the theoretical basis of marine biological resources in the treatment of atherosclerosis.

Ultrasound and Magnetic Responsive Drug Delivery Systems for Cardiovascular Application.

With the increasing insight into molecular mechanisms of cardiovascular disease, a promising solution involves directly delivering genes, cells, and chemicals to the infarcted myocardium or impaired endothelium. However, the limited delivery efficiency after administration fails to reach the therapeutic dose and the adverse off-target effect even causes serious safety concerns. Controlled drug release via external stimuli seems to be a promising method to overcome the drawbacks of conventional drug delivery systems (DDSs). Microbubbles and magnetic nanoparticles responding to ultrasound and magnetic fields respectively have been developed as an important component of novel DDSs. In particular, several attempts have also been made for the design and fabrication of dual-responsive DDS. This review presents the recent advances in the ultrasound and magnetic fields responsive DDSs in cardiovascular application, followed by their current problems and future reformation.

Anti-COVID drugs: repurposing existing drugs or search for new complex entities, strategies and perspectives.

At the end of 2019, a novel virus causing severe acute respiratory syndrome to spread globally. There are currently no effective drugs targeting SARS-CoV-2. In this study, based on the analysis of numerous references and selected methods of computational chemistry, the strategy of integrative structural modification of small molecules with antiviral activity into potential active complex molecules has been presented. Proposed molecules have been designed based on the structure of triterpene oleanolic acid and complemented by structures characteristic of selected anti-COVID therapy assisted drugs. Their pharmaceutical molecular parameters and the preliminary bioactivity were calculated and predicted. The results of the above analyses show that among the designed complex substances there are potential antiviral agents directed mainly on SARS-CoV-2.

Reliable identification of cardiac liability in drug discovery using automated patch clamp: Benchmarking best practices and calibration standards for improved proarrhythmic assessment.

INTRODUCTION: Screening compounds for activity on the hERG channel using patch clamp is a crucial part of safety testing. Automated patch clamp (APC) is becoming widely accepted as an alternative to manual patch clamp in order to increase throughput whilst maintaining data quality. In order to standardize APC experiments, we have investigated the effects on IC50 values under different conditions using several devices across multiple sites. METHODS: APC instruments SyncroPatch 384i, SyncroPatch 384PE and Patchliner, were used to record hERG expressed in HEK or CHO cells. Up to 27 CiPA compounds were used to investigate effects of voltage protocol, incubation time, labware and time between compound preparation and experiment on IC50 values. RESULTS: All IC50 values of 21 compounds recorded on the SyncroPatch 384PE correlated well with IC50 values from the literature (Kramer et al., 2013) regardless of voltage protocol or labware, when compounds were used immediately after preparation, but potency of astemizole decreased if prepared in Teflon or polypropylene (PP) compound plates 2-3 h prior to experiments. Slow acting compounds such as dofetilide, astemizole, and terfenadine required extended incubation times of at least 6 min to reach steady state and therefore, stable IC50 values. DISCUSSION: Assessing the influence of different experimental conditions on hERG assay reliability, we conclude that either the step-ramp protocol recommended by CiPA or a standard 2-s step-pulse protocol can be used to record hERG; a minimum incubation time of 5 min should be used and although glass, Teflon, PP or polystyrene (PS) compound plates can be used for experiments, caution should be taken if using Teflon, PS or PP vessels as some adsorption can occur if experiments are not performed immediately after preparation. Our recommendations are not limited to the APC devices described in this report, but could also be extended to other APC devices.

(Hetero)Aryloxyaminopropanols with N-Phenylpiperazine Structural Fragment - Review of Cardiovascular Activity.

Aryloxyphenylpiperazinylpropanols are a group of compounds exhibiting a wide range of biological activities, affecting the central nervous system and many cardiovascular mechanisms among them. As cardiovascular agents, aryloxyphenylpiperazinylpropanols work as antihypertensives, antiarrhythmics, cardiotonics or antiaggregants. The mechanism of action is almost always an α1-adrenolytic or combined α1- and ß-adrenolytic effect, but sometimes other mechanisms (e.g., Ca2+ antagonism or phosphodiesterase inhibition) can positively participate. In some cases, compounds with a small modification of the connecting chain also exhibit the desired cardiovascular effects. Several studies dealt with chirality of aryloxyphenylpiperazinylpropanols and determined the differences between the particular activities of racemic and enantiomeric compounds.