Identification Of New Chemical Entities Research Articles

Ligandability Assessment of IL-1β by Integrated Hit Identification Approaches.

Human interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a critical role in the regulation of the immune response and the development of various inflammatory diseases. In this publication, we disclose our efforts toward the discovery of IL-1β binders that interfere with IL-1β signaling. To this end, several technologies were used in parallel, including fragment-based screening (FBS), DNA-encoded library (DEL) technology, peptide discovery platform (PDP), and virtual screening. The utilization of distinct technologies resulted in the identification of new chemical entities exploiting three different sites on IL-1β, all of them also inhibiting the interaction with the IL-1R1 receptor. Moreover, we identified lysine 103 of IL-1β as a target residue suitable for the development of covalent, low-molecular-weight IL-1β antagonists.

A combined approach of structure-based virtual screening and NMR to interrupt the PD-1/PD-L1 axis: Biphenyl-benzimidazole containing compounds as novel PD-L1 inhibitors.

Immunotherapy has emerged as a game-changing approach for cancer treatment. Althoughmonoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole-containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time-resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC50 ) in the submicromolar range and notably, differently from the major part of PD-L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole-based compounds as novel promising candidates for PD-L1 inhibition.

Allosteric modulators of solute carrier function: a theoretical framework.

Large-scale drug screening is currently the basis for the identification of new chemical entities. This is a rather laborious approach, because a large number of compounds must be tested to cover the chemical space in an unbiased fashion. However, the structures of targetable proteins have become increasingly available. Thus, a new era has arguably been ushered in with the advent of methods, which allow for structure-based docking campaigns (i.e., virtual screens). Solute carriers (SLCs) are among the most promising drug targets. This claim is substantiated by the fact that a large fraction of the 400 solute carrier genes is associated with human diseases. The ability to dock large ligand libraries into selected structures of solute carriers has set the stage for rational drug design. In the present study, we show that these structure-based approaches can be refined by taking into account how solute carriers operate. We specifically address the feasibility of targeting solute carriers with allosteric modulators, because their actions differ fundamentally from those of ligands, which bind to the substrate binding site. For the pertinent analysis we used transition state theory in conjunction with the linear free energy relationship (LFER). These provide the theoretical framework to understand how allosteric modulators affect solute carrier function.

A Review on the Synthetic Approach of Marinopyrroles: A Natural Antitumor Agent from the Ocean

Natural products play an important role in various drug discovery and development approaches. They are known to be the rich resources for the identification of new chemical entities (NCEs) intended to treat various diseases. Many drugs have been discovered and developed from natural sources. Indeed, collaborative efforts involving biologists as well as organic, medicinal, and phytochemists usually facilitate the identification of potent NCEs derived from natural sources. Over the past 20 years, more than 50% of NCEs have been derived either from marine sources or synthetic/ semisynthetic derivatives of natural products. Indeed, many drug molecules have been designed by considering natural products as the starting scaffold. The first bis-pyrrole alkaloid derivative of marinopyrroles was obtained from the marine-derived streptomycete species. In the laboratory, it can be synthesized via Clauson-Kaas and Friedel-Crafts arylation as well as copper-mediated N-arylation process under microwave irradiation. The marinopyrrole A (±)-28 was discovered to overcome resistance against human cancer cells by antagonizing B-cell lymphoma extra-large (Bcl-xL) and induced myeloid leukaemia cell (Mcl-1). In this review, we elaborated on various synthetic pathways of marinopyrroles possessing anti-cancer potential, which could encourage researchers to discover promising anti-tumor agents.

Identification and optimisation of novel selective inhibitors against human regulator of G protein signalling 2 (RGS2) protein for type 2 diabetes mellitus: an in silico approach

Regulator of G protein signalling 2 (RGS2) protein negatively modulates GPCR signalling pathway causing type 2 diabetes and treated as drug target for the new lead identification. Since RGS2 lacks its experimental structure, the 3D structure of RGS2 protein was built by homology modelling to perform docking studies. The active site of RGS2 protein was identified and virtual screening was carried out by GLIDE docking for the hit identification. Initially, 14 hits were identified, and these hits were further optimised by AutoDock, Prime MM/GBSA, and percent human oral absorption. The druglikeness of newly identified leads was assessed through absorption, distribution, metabolism, excretion (ADME) properties. The comparative binding affinity study of current drugs of diabetes to that of newly identified leads was carried out to justify the potency of new leads against RGS2 protein. Thus, the results of the present study may afford insights into the identification of new chemical entities as potential type 2 diabetes mellitus drug candidates.

NSC 18725, a Pyrazole Derivative Inhibits Growth of Intracellular Mycobacterium tuberculosis by Induction of Autophagy.

The increasing incident rates of drug-resistant tuberculosis (DR-TB) is a global health concern and has been further complicated by the emergence of extensive and total drug-resistant strains. Identification of new chemical entities which are compatible with first-line TB drugs, possess activity against DR-, and metabolically less active bacteria is required to tackle this epidemic. Here, we have performed phenotypic screening of a small molecule library against Mycobacterium bovis BCG and identified 24 scaffolds that exhibited MIC99 values of at least 2.5 μM. The most potent small molecule identified in our study was a nitroso containing pyrazole derivative, NSC 18725. We observed a significant reduction in viable bacilli load of starved Mycobacterium tuberculosis upon exposure to NSC 18725. The action of NSC 18725 was “synergistic” with isoniazid (INH) and “additive” with other drugs in our checkerboard assays. Structure-activity relationship (SAR) studies of the parent compound revealed that pyrazole derivatives without a functional group at fourth position lacked anti-mycobacterial activity in vitro. The derivative with para-chlorophenyl substitution at the first position of the pyrazole ring was the most active scaffold. We also demonstrate that NSC 18725 is able to induce autophagy in differentiated THP-1 macrophages. The induction of autophagy by NSC 18725 is the major mechanism for the killing of intracellular slow and fast-growing mycobacteria. Taken together, these observations support the identification of NSC 18725 as an antimycobacterial compound, which synergizes with INH, is active against non-replicative mycobacteria and induces autophagy in macrophages.

Strategies to Overcome Antimicrobial Resistance (AMR) Making Use of Non-Essential Target Inhibitors: A Review.

Antibiotics have always been considered as one of the most relevant discoveries of the twentieth century. Unfortunately, the dawn of the antibiotic era has sadly corresponded to the rise of the phenomenon of antimicrobial resistance (AMR), which is a natural process whereby microbes evolve in such a way to withstand the action of drugs. In this context, the identification of new potential antimicrobial targets and/or the identification of new chemical entities as antimicrobial drugs are in great demand. To date, among the many possible approaches used to deal with antibiotic resistance is the use of antibiotic adjuvants that hit bacterial non-essential targets. In this review, the author focuses on the discovery of antibiotic adjuvants and on new tools to study and reduce the prevalence of resistant bacterial infections.

Design, synthesis and antibacterial activity evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids

In this work, a series of novel moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l were designed and synthesized. The in vitro antibacterial activity against a panel of clinically important Gram-positive and Gram-negative bacteria including drug-resistant pathogens was also evaluated. All hybrids showed considerable activity against the tested pathogens with MIC values of ≤0.03 to 128 μg/mL, and some of them such as hybrids 7e, 7g and 7j were comparable to or better than the parent moxifloxacin (MIC: ≤0.03–8 μg/mL). Moreover, hybrids 7e, 7g and 7j also demonstrated low cytotoxicity towards CHO cells. However, the in vivo pharmacokinetic profiles of these three hybrids were generally far inferior to the parent moxifloxacin. The structure-activity relationship and structure-cytotoxicity relationship were also studied and discussed which may help with the identification of new chemical entities as potent antibacterial agents.

Ciprofloxacin-1,2,3-triazole-isatin hybrids tethered via amide: Design, synthesis, and in vitro anti-mycobacterial activity evaluation

The purpose of this study was to prepare various novel amide tethered ciprofloxacin-1,2,3-triazole-isatin hybrids 7a-l, and evaluate their in vitro anti-mycobacterial activity as well as cytotoxicity in VERO cells. The synthesized hybrids showed considerable in vitro activity against both MTB H37Rv and MDR-MTB with MIC of 0.12 to 32 μg/mL, and acceptable cytotoxicity in VERO cells (CC50: 8.0->128.0 μg/mL). In particular, the most active hybrid 7a (MICMTB H37Rv: 0.5 μg/mL and MICMDR-MTB: 0.12 μg/mL) had the activity in the same level with the first-line anti-tubercular agents isoniazid (MIC: 0.12 μg/mL) and rifampicin (MIC: 0.25 μg/mL), and it was 2-fold more active than the parent ciprofloxacin (MIC: 1.0 μg/mL) against MTB H37Rv, and ≥16 folds more potent than ciprofloxacin (MIC: 2.0 μg/mL), isoniazid (MIC: >64 μg/mL) and rifampicin (MIC: >64 μg/mL) against MDR-MTB. Moreover, hybrid 7a (CC50: 16.0 μg/mL) also displayed considerable cytotoxicity towards VERO cells. Thus, hybrid 7a could act as a platform for further investigations.

Natural products chemistry: A pathway for drugs discovery

Long before the era of high through-put screening and genomics, drug discovery relied heavily on natural products. Drug discovery involves the identification of New Chemical Entities (NCEs) of potential therapeutic value, which can be obtained through isolation from natural sources, through chemical synthesis or a combination of both. However, the success stories for the discoveries Penicillin from penecilium rubens, Paclitaxel yew tree and marketed as Taxol, Aspirin from Willow bark of Salix alba tree etc. have pave way for scholars in the field of natural product and organic chemistry to focus their research work in drug-derived from plants and microorganisms. Natural products derived from these sources are rich in bioactive compound, which have been use over years throughout human history and evolution as remedies for various ailments. This paper however, X-rayed the sources and classes of natural products, pharmaceuticals derived from Natural product, and uses of natural products. The paper also recommended among others that, government should fund research in the area of natural products, pharmaceutical chemistry and Pharmacognocy.

Synthesis and evaluation of new benzimidazole derivatives with hydrazone moiety as anticancer agents

Abstract Objectives Cancer is one of the leading causes of death throughout the world. Current therapy options suffer from the major limitations of side effects and drug resistance. Thus, continuing search for newer and safer anticancer drugs remains critically important. From this point of view, in the present study benzimidazole-hydrazone derivatives were synthesized by aiming at the identification of new chemical entities as potent anticancer agents. Material and methods A series of 12 new compounds of 4-(5(6)-substituted-1H-benzimidazol-2-yl)-N′thiophen/furan-2-yl-methylene) benzohydrazide derivatives were synthesized. The structures of the obtained compounds were elucidated using by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. In vitro cytotoxic activity of the compounds against A549, MCF-7 and NIH/3T3 cell lines was evaluated by MTT assay. Results Among the tested compounds, compound 3e showed higher cytotoxicity against MCF-7 human breast cancer cells when compared with cisplatin. Also, it has lower cytotoxicty against healthy cell line, NIH/3T3. Conclusions It was determined that compound 3e showed inhibition towards MCF-7. Considering the substituent effect on cytotoxic activity, compound 3e bearing 2-methylthiophene has attracted attention with its higher anticancer activities.

Natural Bioenhancers: Current Outlook

Pharmaceutical companies around the globe have always been in the urge of discovering innovative blockbuster drugs for various ailments by spending billions of dollars for the drug discovery programmes. Although identification of new chemical entities (NCEs) with alternate mode of actions for diseases is a primary concern for the pharmaceutical companies, application of innovative techniques and technologies to increase the bioavailability, efficacy and safety of the already existing drugs are of no less concern as well. In fact, enhancing bioavailability of therapeutically potent but poorly bioavailable molecules has always been a crucial aspect of drug development programmes, as it reduces the drug dosage and frequency resulting in reduced toxicity and cost for the patients [1]. Among the various factors responsible for poor bioavailability of drugs, physiochemical properties of the drug itself and biological barriers are two predominant factors [2]. While physicochemical properties of the drug include poor aqueous solubility, poor intestinal membrane permeability, and poor stability of drug in gastrointestinal tract (GIT), biological barrier constitutes hepatic and intestinal drug metabolizing enzymes (DMEs) and efflux drug transporters (EDTs). The metabolism of drugs by cytochrome P450 (CYP) DMEs in the gut wall and in the liver is the major contributors of reduced bioavailability of drugs that are substrate to these DMEs [3]. In addition to this, EDTs such as P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), multidrug resistant-associated protein (MRP) are also responsible for reduced bioavailability of the therapeutically active drugs, especially anticancer drugs [3].

Biodiversity in production of antibiotics and other bioactive compounds.

Microbes continue to play a highly considerable role in the drug discovery and development process. Nevertheless, the number of new chemical entities (NCEs) of microbial origin that has been approved by the Food and Drug Administration (FDA) has been reduced in the past decade. This scarcity can be partly attributed to the redundancy in the discovered molecules from microbial isolates, which are isolated from common terrestrial ecological units. However, this situation can be partly overcome by exploring rarely exploited ecological niches as the source of microbes, which reduces the chances of isolating compounds similar to existing ones. The use of modern and advanced isolation techniques, modification of the existing fermentation methods, genetic modifications to induce expression of silent genes, analytical tools for the detection and identification of new chemical entities, use of polymers in fermentation to enhance yield of fermented compounds, and so on, have all aided in enhancing the frequency of acquiring novel compounds. These compounds are representative of numerous classes of diverse compounds. Thus, compounds of microbial origin and their analogues undergoing clinical trials continue to demonstrate the importance of compounds from microbial sources in modern drug discovery.

Insights into the Structure and Pharmacology of the Human Trace Amine‐Associated Receptor 1 (hTAAR1): Homology Modelling and Docking Studies

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T(1)AM). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein-agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein-binding site has been explored by comparing the hTAAR1 model with the β(2)-adrenoreceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT(1A) receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T(1)AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.

81: Targeting casein kinase 2 in drug discovery: identification of new chemical entities

81: Targeting casein kinase 2 in drug discovery: identification of new chemical entities

Apports de la chémo-informatique dans la recherche et l’optimisation des molécules d’intérêt thérapeutique

Successful identification of new chemical entities with drug-like properties in pharmaceutical and academic research groups involves an early screen and the use of a large number of public and proprietary chemical libraries. Before applying high-throughput experimental screening approaches, virtual screening strategies have been put in place in order to sort and filter this massive amount of compounds and data available at these very early stages. Chemoinformatic tools have a crucial role in this selection process and enable therapeutic chemists to focus very early on promising candidates. Virtual screening has conventionally been based either on models of the target or the ligand (molecule), but today these models include biopharmaceutical filters addressing right from the start of the project the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of the molecules. Above all, chemoinformatic tools help chemists understand better the chemical diversity they can work with, especially when comparing chemical libraries. This paper will focus on exemples of the day-to-day use of chemoinformatics in screening programs. A large part will be dedicated to new tools (chemographic and pharmacographic approaches) being developed for the representation and analysis of chemical diversity, but also for combining chemical and biological information to expedite research programs.

In silico prediction of mitochondrial toxicity by using GA-CG-SVM approach

Drug-induced mitochondrial toxicity has become one of the key reasons for which some drugs fail to enter market or are withdrawn from market. Thus early identification of new chemical entities that injure mitochondrial function grows to be very necessary to produce safer drugs and directly reduce attrition rate in later stages of drug development. In this study, support vector machine (SVM) method combined with genetic algorithm (GA) for feature selection and conjugate gradient method (CG) for parameter optimization (GA-CG-SVM), has been employed to develop prediction model of mitochondrial toxicity. We firstly collected 288 compounds, including 171 MT+ and 117 MT-, from different literature resources. Then these compounds were randomly separated into a training set (253 compounds) and a test set (35 compounds). The overall prediction accuracy for the training set by means of 5-fold cross-validation is 84.59%. Further, the SVM model was evaluated by using the independent test set. The overall prediction accuracy for the test set is 77.14%. These clearly indicate that the mitochondrial toxicity is predictable. Meanwhile impacts of the feature selection and SVM parameter optimization on the quality of SVM model were also examined and discussed. The results implicate the potential of the proposed GA-CG-SVM in facilitating the prediction of mitochondrial toxicity.

Novel Approaches to Antimalarial Drug Discovery

Major advances in our understanding of malaria parasite biology have been made. Coupled with the completion of the malaria genome, this has presented exciting opportunities for target-based antimalarial drug discovery. However, the unraveling of more validated biological targets will not necessarily translate into the identification of new chemical entities that are effective against drug resistant parasites in the long term. As history has already shown, development of antiplasmodial agents aimed at a single parasite target or specialized process has failed to stem the tide of drug resistance. This review highlights recent starting points and/or approaches to antimalarial drug discovery with particular emphasis on innovative efforts, which are not necessarily based on the identification of new drug targets and attendant inhibitor design. Approaches covered include utilization of validated chemical scaffolds, bioprecursor and carrier prodrugs, double drug development and/or multi-therapeutic strategies, use of metallocenic scaffolds, the medicinal chemistry of antimalarial natural products and in silico drug design.

Investigation of Drug-Induced Mitochondrial Toxicity Using Fluorescence-Based Oxygen-Sensitive Probes

Mitochondrial dysfunction is a common mechanism of drug-induced toxicity. Early identification of new chemical entities (NCEs) that perturb mitochondrial function is of significant importance to avoid attrition in later stages of drug development. One of the most informative ways of assessing mitochondrial dysfunction is by measuring mitochondrial oxygen consumption. However, the conventional polarographic method of measuring oxygen consumption is not amenable to high sample throughput or automation. We present an alternative, low-bulk, high-throughput approach to the analysis of isolated-mitochondrial oxygen consumption using luminescent oxygen-sensitive probes. These probes are dispensable and are analyzed in standard microtitre plates on a fluorescence plate reader. Respiratory substrate and adenosine diphosphate (ADP) dependencies of mitochondrial oxygen consumption were assessed using the fluorescence-based method, and results compared favourably to conventional polarographic analysis. To assess assay performance, the method was then applied to the analysis of a panel of classical modulators of oxidative phosphorylation. The effect of uncoupler concentration was analyzed in detail to identify factors which would be important in applying this method to large scale NCE screening and mechanistic investigations. Results demonstrate that the 96-well format can accommodate up to approximately 200 compounds/day at a single concentration or alternatively IC(50) values can be generated for approximately 25 compounds. Throughput may be increased by moving to a 384-well plate format.