Design Of New Drug Candidates Research Articles

New 1H-benzimidazole-2-yl hydrazones with combined antiparasitic and antioxidant activity.

Parasitic infections, caused mainly by the species Trichinella spiralis (T. spiralis), are widespread around the world and lead to morbidity and mortality in the population. Meanwhile, some studies have showed that these parasites induce oxidative stress in the infected host. With the aim of developing a class of compounds combining anthelmintic with antioxidant properties, a series of new benzimidazolyl-2-hydrazones 5a-l, bearing hydroxyl- and methoxy-groups, were synthesized. The anthelmintic activity on encapsulated T. spiralis was studied in vitro thus indicating that all hydrazones were more active than the clinically used anthelmintic drugs albendazole and ivermectin. 5b and 5d killed the total parasitic larvae (100% effectiveness) after 24 hours incubation period at 37 °C in both concentrations (50 and 100 μg ml−1). The antioxidant activity of the target compounds was elucidated in vitro against stable free radicals DPPH and ABTS as well as iron induced oxidative damage in model systems containing biologically relevant molecules lecithin and deoxyribose. The two 2,3- and 3,4-dihydroxy hydrazones 5b and 5d were the most effective radical scavengers in all studied systems. DFT calculations were applied to calculate the reaction enthalpies in polar and nonpolar medium and estimate the preferred mechanism of antioxidant activity. The relative radical scavenging ability of compounds 5a-l showed a good correlation to the experimentally observed trends. It was found that the studied compounds are capable to react with various free radicals – ˙OCH3, ˙OOH and ˙OOCH3, through several possible reaction pathways – HAT in nonpolar medium, SPLET in polar medium and RAF in both media.

Prediction of Sars-Cov-2 Main Protease Potential Inhibitors from Libyan Arbutus Pavarii Pampan Compounds: A Molecular Docking Study

The present study examined some natural active compounds contained in the Libyan Arbutus pavarii Pampan. shrub that might be used as natural inhibitors of SARS-CoV-2, the responsible causative agent of coronavirus disease 2019 (COVID-19). A molecular docking method was employed to find out the capability of the selected molecules to interact with the virus main protease. Seven flavonoids from twenty-seven compounds belonging to different classes showed a remarkable ability to bind to the main protease of the novel coronavirus. The descending order of compounds with the highest binding affinity was as follows: Saponarin, Rutin, Delphinidin3-rutinoside, Neodiosmin, Kampferol-3-O-ß-D-rutinoside, Isoquercetin, and Hyperoside. The outcomes have provided a clear insight into the structure-activity relationship of Mpro targeting agents and may assist the future design of new drug candidates for the disease.

Researchers are betting that AI and automation can cut drug discovery from five years to six months: Automating antivirals

WITHIN MOMENTS OF MEETING EACH OTHER at a conference last year, Nathan Collins and Yann Gaston-Mathe began devising a plan to work together. Gaston-Mathe runs a startup that applies automated software to the design of new drug candidates. Collins leads a team that uses an automated chemistry platform to synthesize new drug candidates. • “There was an obvious synergy between their technology and ours,” recalls Gaston-Mathe, CEO and cofounder of Paris-based Iktos. • In late 2019, the pair launched a project to create a brand-new antiviral drug that would block a specific protein exploited by influenza viruses. Then the COVID-19 pandemic erupted across the world stage, and Gaston-Mathe and Collins learned that the viral culprit, SARS-CoV-2, relied on a protein that was 97 percent similar to their influenza protein. The partners pivoted. • Their companies are just two of hundreds of biotech firms eager to overhaul the drug-discovery process, often with the aid of artificial intelligence (AI) tools. The first set of antiviral drugs to treat COVID-19 will likely come from sifting through existing drugs. Remdesivir, for example, was originally developed to treat Ebola, and it has been shown to speed the recovery of hospitalized COVID-19 patients. But a drug made for one condition often has side effects and limited potency when applied to another. If researchers can produce an antiviral that specifically targets SARS-CoV-2, the drug would likely be safer and more effective than a repurposed drug.

Driving antimalarial design through understanding of target mechanism.

Malaria continues to be a global health threat, affecting approximately 219 million people in 2018 alone. The recurrent development of resistance to existing antimalarials means that the design of new drug candidates must be carefully considered. Understanding of drug target mechanism can dramatically accelerate early-stage target-based development of novel antimalarials and allows for structural modifications even during late-stage preclinical development. Here, we have provided an overview of three promising antimalarial molecular targets, PfDHFR, PfDHODH and PfA-M1, and their associated inhibitors which demonstrate how mechanism can inform drug design and be effectively utilised to generate compounds with potent inhibitory activity.

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases.

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

Mycobacterial drug discovery

Mycobacterium tuberculosis is the causative pathogen of the pulmonary disease tuberculosis. Despite the availability of effective treatment programs, there is a global pursuit of new anti-tubercular agents to respond to the developing threat of drug resistance, in addition to reducing the extensive duration of chemotherapy and any associated toxicity. The route to mycobacterial drug discovery can be considered from two directions: target-to-drug and drug-to-target. The former approach uses conventional methods including biochemical assays along with innovative computational screens, but is yet to yield any drug candidates to the clinic, with a high attrition rate owing to lack of whole cell activity. In the latter approach, compound libraries are screened for efficacy against the bacilli or model organisms, ensuring whole cell activity, but here subsequent target identification is the rate-limiting step. Advances in a variety of scientific fields have enabled the amalgamation of aspects of both approaches in the development of novel drug discovery tools, which are now primed to accelerate the discovery of novel hits and leads with known targets and whole cell activity. This review discusses these traditional and innovative techniques, which are widely used in the quest for new anti-tubercular compounds.

Interpretative considerations for clinical pathology findings in nonclinical toxicology studies.

The interpretation of clinical pathology results from nonclinical safety studies is a fundamental component in hazard identification of new drug candidates. The ever-increasing complexity of nonclinical safety studies and sophistication of modern analytical methods have made the interpretation of clinical pathology information by a highly trained subject matter expert imperative. Certain interpretive techniques are particularly effective in the identification and characterization of clinical pathology effects. The purpose of this manuscript is to provide an overview of contemporary interpretive practices for clinical pathology results and to provide nonbinding recommendations aimed at improving consistency, quality, and overall value of clinical pathology interpretations generated in support of nonclinical toxicology studies.

Internet Resources for Drug Discovery and Design.

The review describes online resources used for drug discovery and design. Internet resources can be classified into two classes. The first class of resources accumulates information about drugs, drug candidates, compounds, and bioassays. This information is a starting point in drug discovery and design. It is necessary for a training dataset composition. The data found at this step are needed in the search for the rules predicting a biological activity or recognizing active compounds among other molecules. The following databases can be used: ChEMBL, different databases of US National Institutes of Health, DrugBank, PDBind-CN Database, RCSB Protein Data Bank (PDB), BRENDA, etc. The second class of Internet resources includes web-portals performing online computations for drug discovery and design. The web-portals perform: 1) modelling of molecular structure such as geometry optimization and molecular docking; 2) online computations of various descriptors, physical-chemical and ADMET properties influencing the bioprocesses occurring in a living organism along the road of the drug therapeutic action; 3) quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) studies; 4) prognosis of bioactivities of compounds; 5) design of new drug candidates. These are, for example, ChemAxon, ACD/ I-lab, Mcule, OCHEM, eADMET, ChemoSophia, DockingServer, 1-click Docking, MDWeb, DockingServer, ZDOCK, etc. The role of docking online resources for modeling of "ligand-receptor" complexes, prognosis of bioactivities, and drug design is discussed. The review highlights the possibilities of Internet resources for a study of a drug action at the most important stages. A detailed assessment of the advantages of the reviewed Internet resources is done.

A review on HCV inhibitors: Significance of non-structural polyproteins

Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130–150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.

Droplet-based Microfluidic Platform for Intracellular Ion Channel Drug Discovery - EPSRC

New technology is widening the chance of developing new pharmacological compounds and has the potential to create new jobs and have economic and societal impact on healthcare. Economic impact: The average expenditure to develop and bring to market a new drug is estimated to be approximately $2 billion, with target identification, discovery and the development of a new chemical compound before clinical trials accounting for 30% of the total cost. Commercialization of the developed platform has potential to add considerable information over the gold standard obtained by current electrophysiological tests with automated patch-clamp technology and impact the pre-screening stages of compounds, most of which is currently provided as a service by CROs and/or CMOs. Therefore, outcomes from this project have potential to carve a unique sector in the market of drug screening instrumentation. To assess this impact and available opportunities, we have secured the participation of members from academia, healthcare technology and industry to act as an advisory board for consultancy regarding knowledge transfer and commercialisation. Industrial impact: The developed system will be tested in collaboration with project partner Apconix for the development of pharmacological assays based on combinatorial chemistry approaches. Outside the immediate benefit in identifying new active compounds for the CLIC4 channel, the potential for translating the developed procedures for other pharmacologically relevant eukaryotic ion channels present cost-saving arguments against current live-cell based, large-screening assay in the Pharmaceutical industry. In addition, the collaboration with project partner Smartox will explore a further application of the technology for use with limited resources of venom samples only available in extremely small quantities that currently elude industrial automated screening. The proposed technology has the potential to greatly impact drug discovery by identifying new efficient venom-derived drugs. Together, this double partnership will enable us to address different screening needs for both SME and the Pharmaceutical Industry. Societal impact: Identification of new drug candidates from the developed technology will expand the panel of drugs with implications in cancer, mitochondrial dysfunction and neurodegenerative diseases. Improving the efficacy of identified drugs at preclinical level is expected to improve outcomes during clinical trials. Therefore, wide societal benefits would be in the form of new medicine and their improved efficacy. Furthermore, the applicability of the proposed technology to the other identified applications (see academic beneficiaries) and healthcare related fields could impact the screening of vaccines and environmental toxins, all of which will produce massive societal benefits.

Multi-Target Directed Drugs as a Modern Approach for Drug Design Towards Alzheimer's Disease: An Update.

Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Identification of new benzamide inhibitor against α-subunit of tryptophan synthase from Mycobacterium tuberculosis through structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations

Multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis has emerged as global health threat, causing millions of deaths worldwide. Identification of new drug candidates for tuberculosis (TB) by targeting novel and less explored protein targets will be invaluable for antituberculosis drug discovery. We performed structure-based virtual screening of eMolecules database against a homology model of relatively unexplored protein target: the α-subunit of tryptophan synthase (α-TRPS) from Mycobacterium tuberculosis essential for bacterial survival. Based on physiochemical properties analysis and molecular docking, the seven candidate compounds were selected and evaluated through whole cell-based activity against the H37Rv strain of M. tuberculosis. A new Benzamide inhibitor against α-subunit of tryptophan synthase (α-TRPS) from M. tuberculosis has been identified causing 100% growth inhibition at 25 μg/ml and visible bactericidal activity at 6 μg/ml. This benzamide inhibitor displayed a good predicted binding score (−48.24 kcal/mol) with the α-TRPS binding pocket and has logP value (2.95) comparable to Rifampicin. Further refinement of docking results and evaluation of inhibitor-protein complex stability were investigated through Molecular dynamic (MD) simulations studies. Following MD simulations, Root mean square deviation, Root mean square fluctuation and secondary structure analysis confirmed that protein did not unfold and ligand stayed inside the active pocket of protein during the explored time scale. This identified benzamide inhibitor against the α-subunit of TRPS from M. tuberculosis could be considered as candidate for drug discovery against TB and will be further evaluated for enzyme-based inhibition in future studies.

The Contribution of Studies with Canabidiol and Synthetic Analogues in the Design of New Drug Candidates for Neuropsychiatric Disorders and Neurodegenerative Diseases

O primeiro uso documentado da Cannabis para fins terapeuticos aparece por volta de 2300 a.C., para o tratamento de constipacao, gota, beriberi, malaria, reumatismo e problemas menstruais. A busca por efeitos terapeuticos a partir da Cannabis ja ocupa os cientistas ha mais de 50 anos, sendo que nos ultimos 10 anos, foi iniciada uma nova fase de estudos acerca dos componentes da maconha, a exemplo do ? 9 -tetraidrocanabinol (THC, 1 ) e do canabidiol (CBD, 2 ) para uso medicamentoso. O CBD ocorre em cerca de 40% no extrato bruto de Cannabis sativa , alem de outros 60 tipos de canabinoides e inumeros constituintes nao-canabinoides, totalizando cerca de 300 metabolitos secundarios. O CBD, apesar de ser um constituinte da Cannabis e desprovido dos efeitos tipicos da planta, diferentemente do THC que induz a ansiedade e efeitos psicoticos, sendo o principal ingrediente psicoativo. Estudos sugerem que o CBD possa atuar no cerebro como modulador do THC , podendo ter efeitos ansioliticos e/ou antipsicoticos, antagonizando alguns efeitos indesejaveis do THC, alem de contribuir com propriedades analgesicas, antiemeticas e antineoplasicas, afetar a plasticidade sinaptica e facilitar a neurogenese. Neste contexto, a literatura cientifica fortalece a necessidade de avancos e investimentos em pesquisa nesta area, buscando um melhor entendimento do sistema endocanabinoide e a busca por novos canabinoides naturais e sinteticos, visando sua aplicacao clinica e ampliacao do arsenal terapeutico disponivel para doencas psiquicas e neurodegenerativas. Os dados mais recentes de estudos voltados ao melhor entendimento de sua farmacologia e da potencial aplicacao terapeutica sugerem que o CBD e seus analogos possam desempenhar papel singular na modulacao de alvos moleculares envolvidos em disfuncoes do sistema nervoso central, possibilitando o desenvolvimento de farmacos inovadores, mais seguros e eficazes no tratamento de pacientes nao-responsivos a clinica convencional, com melhora significativa na qualidade de vida e, quica, sua cura.

ChemInform Abstract: 8‐Hydroxyquinolines in Medicinal Chemistry: A Structural Perspective

AbstractReview: 200 refs.

Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening.

Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%–20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved) that were screened are Library of Pharmacologically Active Compounds (LOPAC1280), the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150 unique compounds, which inhibited >90% of B. burgdorferi growth at a concentration of <25 µM. These 150 unique compounds comprise many safe antibiotics, chemical compounds, and also small molecules from plant sources. Of the 150 unique compounds, 101 compounds are FDA approved. We selected the top 20 FDA-approved molecules based on safety and potency and studied their minimum inhibitory concentration and minimum bactericidal concentration. The promising safe FDA-approved candidates that show low minimum inhibitory concentration and minimum bactericidal concentration values can be chosen as lead molecules for further advanced studies.

Software-aided structural elucidation in drug discovery.

Structural information on metabolites obtained in relevant biological systems can have considerable impact on the design of new drug candidates. However, with demanding turnaround times, the amount of available structural information may become rate limiting. The workflow for metabolite identification used in our laboratory was compared to a workflow using a software tool built for computer-assisted metabolite identification. The present study covered the in vitro metabolism of a diverse set of 65 in-house compounds. The compounds were profiled across three liver-based systems, 17 compounds were tested in human liver microsomes (HLM), 12 in rat hepatocytes (RHEP), and 36 in human hepatocytes (HHEP). For 92% of the metabolites reported, the exact match or Markush representations were in agreement between the two workflows. The major specific biotransformations in hepatocytes which formed the metabolites were aromatic or aliphatic hydroxylations (33%), N-dealkylations (15%) and glucuronidations (12%). The software was shown to perform well for structural elucidation of metabolites from both phase I and phase II metabolism where the focus was on quickly understanding the rate-limiting metabolic step(s).

ChemInform Abstract: Total Syntheses of Heliannuols: An Overview

AbstractReview: [41 refs.

Insight into the interactions between novel coumarin derivatives and human A3 adenosine receptors.

A study focused on the discovery of new chemical entities based on the 3-arylcoumarin scaffold was performed with the aim of finding new adenosine receptor (AR) ligands. Thirteen synthesized compounds were evaluated by radioligand binding (A1, A2A, and A3) and adenylyl cyclase activity (A2B) assays in order to study their affinity for the four human AR (hAR) subtypes. Seven of the studied compounds proved to be selective A3 AR ligands, with 3-(4'-methylphenyl)-8-(2-oxopropoxy)coumarin (12) being the most potent (Ki =634 nM). None of the compounds showed affinity for the A2B receptor, while four compounds were found to be nonselective AR ligands for the other three subtypes. Docking simulations were carried out to identify the hypothetical binding mode and to rationalize the interaction of these types of coumarin derivatives with the binding site of the three ARs to which binding was observed. The results allowed us to conclude that the 3-arylcoumarin scaffold composes a novel and promising class of A3 AR ligands. ADME properties were also calculated, with the results suggesting that these compounds are promising leads for the identification of new drug candidates.

Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far, the therapeutic paradigm “one-compound-one-target” has failed and despite enormous efforts to elucidate the pathophysiology of AD, the disease is still incurable. The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of Aβ, hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction and deterioration of synaptic transmission. These factors together, accentuate changes in the CNS homeostasis, starting a complex process of interconnected physiological damage, leading to cognitive and memory impairment and neuronal death. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligand (MTDL) approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compounds acting simultaneously on diverse biological targets. This review aims to show some recent advances and examples of the exploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Energy metabolism and metabolic sensors in stem cells: the metabostem crossroads of aging and cancer.

We are as old as our adult stem cells are; therefore, stem cell exhaustion is considered a hallmark of aging. Our tumors are as aggressive as the number of cancer stem cells (CSCs) they bear because CSCs can survive treatments with hormones, radiation, chemotherapy, and molecularly targeted drugs, thus increasing the difficulty of curing cancer. Not surprisingly, interest in stem cell research has never been greater among members of the public, politicians, and scientists. But how can we slow the rate at which our adult stem cells decline over our lifetime, reducing the regenerative potential of tissues, while efficiently eliminating the aberrant, life-threatening activity of "selfish", immortal, and migrating CSCs? Frustrated by the gene-centric limitations of conventional approaches to aging diseases, our group and other groups have begun to appreciate that bioenergetic metabolism, i.e., the production of fuel & building blocks for growth and division, and autophagy/mitophagy, i.e., the quality-control, self-cannibalistic system responsible for "cleaning house" and "recycling the trash", can govern the genetic and epigenetic networks that facilitate stem cell behaviors. Indeed, it is reasonable to suggest the existence of a "metabostem" infrastructure that operates as a shared hallmark of aging and cancer, thus making it physiologically plausible to maintain or even increase the functionality of adult stem cells while reducing the incidence of cancer and extending the lifespan. This "metabostemness" property could lead to the discovery of new drugs that reprogram cell metabotypes to increase the structural and functional integrity of adult stem cells and positively influence their lineage determination, while preventing the development and aberrant function of stem cells in cancer tissues. While it is obvious that the antifungal antibiotic rapamycin, the polyphenol resveratrol, and the biguanide metformin already belong to this new family of metabostemness-targeting drugs, we can expect a rapid identification of new drug candidates (e.g., polyphenolic xenohormetins) that reverse or postpone "geroncogenesis", i.e., aging-induced metabolic decline as a driver of tumorigenesis, at the stem cell level.