Scaffold Hopping Research Articles

Discovery of 2-(1-(3-Chloro-4-cyanophenyl)-1H-pyrazol-3-yl)acetamides as Potent, Selective, and Orally Available Antagonists Targeting the Androgen Receptor.

The androgen receptor (AR) antagonists are efficient therapeutics for the treatment of prostate cancer (PCa). All the approved AR antagonists to date are targeted to the ligand-binding pocket (LBP) of AR and have suffered from various drug resistances, whereas AR antagonist targeting non-LBP site of AR is conceived as a promising strategy. Through the scaffold hopping of AR LBP antagonists, the 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile was designed as a new core structure for AR antagonists. A total of 46 compounds were synthesized and biologically evaluated to disclose compounds 2f, 2k, and 4c, exhibiting potent AR antagonistic activities (IC50 up to 69 nM), force against antiandrogen resistance, and untraditional targeting site of probably AR binding function 3. Therein, 4c exhibited effective tumor growth inhibition in LNCaP xenograft study upon oral administration. This work provides a novel chemical scaffold for AR antagonists and offers new perspective for the development of PCa therapy.

Design of a Structurally Novel Multipotent Drug Candidate by the Scaffold Architecture Technique for ACE-II, NSP15, and Mpro Protein Inhibition: Identification and Isolation of a Natural Product to Prevent the Severity of Future Variants of Covid 19 and a Colorectal Anticancer Drug.

Scaffold architecture in the sectors of biotechnology and drug discovery research include scaffold hopping and molecular modelling techniques and helps in searching for potential drug candidates containing different core structures using computer-based software, which greatly aids medicinal and pharmaceutical chemistry. Going ahead, the computational method of scaffold architecture is thought to produce new scaffolds, and the method is capable of helping search engines toward producing new scaffolds that are likely to represent potent compounds with high therapeutic applications, which is a possibility in this case as well. Here we probate a different interactive design by natural product hopping, molecular modelling, pharmacophore modelling, modification, and combination of the phytoconstituents present in different medicinal plants for developing a pharmacophore-guided good drug candidate for the variants of SARS-CoV-2 or Covid 19. In the modern era, these approaches are carried out at every level of development of scaffold queries, which are increasingly summarized from chemical structures. In this context, we report on a successfully designed drug-like candidate having a high-binding-affinity “compound SLP” by understanding the relationships between the compounds’ pharmacophores, scaffold functional groups, and biological activities beyond their individual applications that abide by Lipinski’s rule of five, Ghose rule, Veber rule etc. The new scaffold generated by altering the core of the known phyto-compounds holds a good predicted ADMET profile and is examined with iMODS server to check the molecular dynamics simulation with normal mode analysis (NMA). The scaffold’s three-dimensional (3D) structure yields a searchable natural product koenimbine from a conformer database having good ADMET property and high availability in spice Murraya koenigii leaves. M. koenigii leaves are easily available in the market, and might ensure the immunity, good health, and well-being of people if affected with any of the variants of Covid 19. The cell viability studies of koenimbine on murine colorectal carcinoma cell line (CT-26) showed no toxicity on normal mice lymphocyte cells (MLCs). The anticancer mechanism of koenimbine was displayed by its enhanced capacity to produce intercellular reactive oxygen species (ROS) in the colorectal carcinoma cell line.

Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors

Aiming to develop novel tropomyosin receptor kinase A (TrkA) inhibitors, a scaffold hopping strategy was utilized by transforming the fused indazole of Entrectinib to phenyl triazole/thiazole skeleton to obtain compounds 7a-7 h and 13a-13 h. In the light of MTT assay, phenyl triazole derivatives 7a-7 h exhibited moderate anti-proliferative activities against KM-12 cells with the IC50 values of 1.78–17.51 μM, while phenyl thiazole derivatives 13a-13 h showed the weaker efficacy. Further structure-guided optimizations by combining the phenyl triazole skeleton with 3,5‑difluorophenyl and 3-carbamoyl-4-piperazinylaniline moiety led to compounds 19a-19d and 20. Eventually, 19c bearing (2-(4-methylpiperazin-1-yl)phenyl)(morpholino)methanone moiety exhibited excellent anti-proliferative activity on TrkA-positive KM-12 cells with IC50 value of 0.17 μM. Meanwhile, compound 19c showed the inhibitory potency on TrkA with IC50 value of 1.6 nM, and displayed higher selectivity on TrkA over TrkB (IC50 = 12.3 nM) and TrkC (IC50 = 18.4 nM). The dedicated wound healing and colony formation assay indicated that the optimal compound 19c could suppress migration and significantly inhibit KM-12 cell colony formation in a dose-dependent manner. In addition, 19c could weakly induce apoptosis of KM-12 cell in immunofluorescent staining analysis. Taken together, the above results suggest 19c as a novel TrkA inhibitor worthy of further profiling.

In silico studies on recreational drugs: 3D quantitative structure activity relationship prediction of classified and de novo designer benzodiazepines.

Currently, increasing availability and popularity of designer benzodiazepines (DBZDs) constitutes a primary threat to public health. To assess this threat, the biological activity/potency of DBZDs was investigated using in silico studies. Specific Quantitative Structure Activity Relationship (QSAR) models were developed in Forge™ for the prediction of biological activity (IC50 ) on the γ-aminobutyric acid A receptor (GABA-AR) of previously identified classified and unclassified DBDZs. A set of new potential ligands resulting from scaffold hopping studies conducted with MOE® was also evaluated. Two generated QSAR models (i.e. 3D-field QSAR and RVM) returned very good performance statistics (r2 =0.98 [both] and q2 =0.75 and 0.72, respectively). The DBZDs predicted to be the most active were flubrotizolam, clonazolam, pynazolam and flucotizolam, consistently with whatreported in literature and/or drug discussion fora. The scaffold hopping studies strongly suggest that replacement of the pendant phenyl moiety with a five-membered ring could increase biological activity and highlight the existence of a still unexplored chemical space for DBZDs. QSAR could be of use as a preliminary risk assessment model for (newly) identified DBZDs, as well as scaffold hopping for the creation of computational libraries that could be used by regulatory bodies as support tools for scheduling procedures.

De Novo Prediction of Drug Targets and Candidates by Chemical Similarity-Guided Network-Based Inference.

Identifying drug–target interactions is a crucial step in discovering novel drugs and for drug repositioning. Network-based methods have shown great potential thanks to the straightforward integration of information from different sources and the possibility of extracting novel information from the graph topology. However, despite recent advances, there is still an urgent need for efficient and robust prediction methods. Here, we present SimSpread, a novel method that combines network-based inference with chemical similarity. This method employs a tripartite drug–drug–target network constructed from protein–ligand interaction annotations and drug–drug chemical similarity on which a resource-spreading algorithm predicts potential biological targets for both known or failed drugs and novel compounds. We describe small molecules as vectors of similarity indices to other compounds, thereby providing a flexible means to explore diverse molecular representations. We show that our proposed method achieves high prediction performance through multiple cross-validation and time-split validation procedures over a series of datasets. In addition, we demonstrate that our method performed a balanced exploration of both chemical ligand space (scaffold hopping) and biological target space (target hopping). Our results suggest robust and balanced performance, and our method may be useful for predicting drug targets, virtual screening, and drug repositioning.

Introduction to Bioisosteric Replacement and Scaffold Hopping in Crop Protection Research.

Introduction to Bioisosteric Replacement and Scaffold Hopping in Crop Protection Research.

Discovery of novel 1,2,4-triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein.

Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC50 values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF-74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF-6 for binding to CA hexamers with IC50 value of 33.4 nM. Like PF-74, d19 inhibits the replication of HIV-1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV-1 CA and rationale for improved affinity and potency over PF-74. Overall, the lead compound d19 displays a distinct chemotype form PF-74, improved CA affinity, and anti-HIV potency.

Design, synthesis and biological evaluation of novel dihydrobenzodioxine derivatives as HBV capsid protein inhibitors

Capsid assembly modulators (CAMs) have recently been revealed to be effective in blocking HBV replication. HBV capsid protein inhibitors reduce and ultimately eliminate HBV by inhibiting virus replication and blocking hepatocyte infection. Sulfonamides are synthetic functional groups in development of different kinds of drugs. Sulfonyl benzamide clinical drugs NVR 3-778 and BA-38017 are lead compounds in discovery of antiviral compounds with increased activity and reduced cytotoxicity by drug design strategies including pharmacophore hybrid, bioisosterism and scaffold hopping. In current study, three series of target compounds were synthesized, and their anti-HBV activity was evaluated against HepAD38 cells. Compound 5a (EC50 = 0.50 ± 0.07 μM, CC50 = 48.16 ± 9.15 μM) showed better anti-HBV DNA replication activity than the lead compound BA-38017, and showed good inhibitory effect on the assembly of HBV capsid protein compared with the clinical drug NVR 3-778. In addition, preliminary structure–activity relationship (SAR) and molecular docking studies were conducted to explore potential interactions and binding modes between compounds and target proteins, which may help researchers to find more effective anti-HBV drugs.

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy

Gamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were tested on the K1 multi-resistant strain of Plasmodium falciparum and the human HepG2 cell-line, to evaluate their antiplasmodial activity and their cytotoxicity. Analogues’ biological results also highlighted the mandatory presence of a heteroatom at position 5 of the thieno[3,2-d]pyrimidin-4(3H)-one moeity for the antiplasmodial activity. However, modifications at position 7 were detrimental for the antiplasmodial activity. We identified furane bioisostere 3j as a promising candidate, showing good blood stage antiplasmodial activity, better water solubility and highly improved intestinal permeability in the PAMPA assay.

Implications of Additivity and Nonadditivity for Machine Learning and Deep Learning Models in Drug Design

Matched molecular pairs (MMPs) are nowadays a commonly applied concept in drug design. They are used in many computational tools for structure–activity relationship analysis, biological activity prediction, or optimization of physicochemical properties. However, until now it has not been shown in a rigorous way that MMPs, that is, changing only one substituent between two molecules, can be predicted with higher accuracy and precision in contrast to any other chemical compound pair. It is expected that any model should be able to predict such a defined change with high accuracy and reasonable precision. In this study, we examine the predictability of four classical properties relevant for drug design ranging from simple physicochemical parameters (log D and solubility) to more complex cell-based ones (permeability and clearance), using different data sets and machine learning algorithms. Our study confirms that additive data are the easiest to predict, which highlights the importance of recognition of nonadditivity events and the challenging complexity of predicting properties in case of scaffold hopping. Despite deep learning being well suited to model nonlinear events, these methods do not seem to be an exception of this observation. Though they are in general performing better than classical machine learning methods, this leaves the field with a still standing challenge.

4-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine Derivatives: Design, Synthesis, Insecticidal Assay and Binding Mode Studies.

A series of 4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized based on the fipronil low energy conformation by scaffold hopping strategy. Physicochemical properties calculation, insecticidal assay and binding mode studies were also performed. It was found that the target compounds displayed lower insecticidal activities than fipronil. The differences in binding modes between these compounds and fipronil may be the major reason for reduced insecticidal activities.

Optimizing the Sunitinib for cardio-toxicity and thyro-toxicity by scaffold hopping approach.

The online version contains supplementary material available at 10.1007/s40203-022-00125-1.

N-Hetaryl-[2(1H)-pyridinyliden]cyanamides: A New Class of Systemic Insecticides.

The new chemical class N-hetaryl-[2(1H)-pyridinylidene]cyanamides were inspired by the long known five-ring structure 2-chloro-5-[2-(nitro-methylene)-1-imidazolidinyl]-pyridine (Shell) and the current development candidate flupyrimin (Meiji Seika Pharma) via scaffold hopping and the concept for designing "shortened structures" by omitting the "methylene link" as a structural feature. The most active N-hetaryl-[2(1H)-pyridinylidene]cyanamides can be synthesized on a technical scale by a simple manufacturing procedure. As full nicotinic acetylcholine receptor (nAChR) agonists, the compounds bind with low affinity at the orthosteric binding site of nAChR. In molecular modeling studies, structural differences are visible in the superposition of active N-[6'-(trifluoromethyl)[1(2H),3'-bipyridin]-2-ylidene]cyanamide onto imidacloprid (IMD) and sulfoxaflor (SXF) in bound conformation. On the basis of their physicochemical properties, the most active xylem systemic candidates offer excellent aphicidal activity in vegetables and cotton, when applied as a foliar spray, by soil drench application, or, in particular, as seed dressing for seed treatment uses. Selected candidates show good plant compatibility and reveal a better risk profile with respect to bee pollinators than the majority of currently registered nAChR competitive modulators for seed treatment uses. Applied as a seed dressing in greenhouse profiling, good to excellent control of different aphid species has been observed. In field trials, an interesting level of activity potential against cereal grain aphids (inclusive virus vector control), corn rootworm, and wireworm could be demonstrated. According to molecular modeling investigations (Fukui functions, dipole moments, and electrostatic potentials), there is a broad scope for structure optimization of the chemical class leading to proposals for novel bicyclic insecticides.

Local Anesthetics via Multicomponent Reactions.

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage-gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)-based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single-crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three-component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.

Discovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis.

Osteoarthritis (OA) treatment is a highly unmet medical need. Development of a disease-modifying OA drug (DMOAD) is challenging with no approved drugs on the market. Inhibition of ADATMS-4/5 is a promising OA therapeutics to target cartilage degradation and potentially can reduce joint pain and restore its normal function. Starting from the reported ADAMTS-5 inhibitor GLPG1972, we applied a scaffold hopping strategy to generate a novel isoindoline amide scaffold. Representative compound 18 showed high potency in ADATMS-4/5 inhibition, as well as good selectivity over a panel of other metalloproteases. In addition, compound 18 exhibited excellent druglike properties and showed better pharmacokinetic (PK) profiles than GLPG1972 cross-species. Compound 18 demonstrated dose-dependent efficacy in two in vivo rat osteoarthritis models.

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase.

The therapeutic challenges pertaining to leishmaniasis due to reported chemoresistance and toxicity necessitate the need to explore novel pathways to identify plausible inhibitory molecules. Leishmania donovani 24-sterol methyltransferase (LdSMT) is vital for the synthesis of ergosterols, the main constituents of Leishmania cellular membranes. So far, mammals have not been shown to possess SMT or ergosterols, making the pathway a prime candidate for drug discovery. The structural model of LdSMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors via virtual screening, scaffold hopping, and de-novo fragment-based design. Altogether, six potential novel inhibitors were identified with binding energies ranging from −7.0 to −8.4 kcal/mol with e-LEA3D using 22,26-azasterol and S1–S4 obtained from scaffold hopping via the ChEMBL, DrugBank, PubChem, ChemSpider, and ZINC15 databases. These ligands showed comparable binding energy to 22,26-azasterol (−7.6 kcal/mol), the main inhibitor of LdSMT. Moreover, all the compounds had plausible ligand efficiency-dependent lipophilicity (LELP) scores above 3. The binding mechanism identified Tyr92 to be critical for binding, and this was corroborated via molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The ligand A1 was predicted to possess antileishmanial properties with a probability of activity (Pa) of 0.362 and a probability of inactivity (Pi) of 0.066, while A5 and A6 possessed dermatological properties with Pa values of 0.205 and 0.249 and Pi values of 0.162 and 0.120, respectively. Structural similarity search via DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the de-novo compounds could be explored as potential antileishmanial agents.

Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy.

Cancer cells can effectively suppress the natural immune response in humans, and prostaglandin E2 (PGE2) is a key mediator in the development of tumor cell resistance to immunotherapy. As a major contributor to PGE2-elicited immunosuppressive activity, the EP4 receptor promotes tumor development and progression in the tumor microenvironment, and the development of selective and potent EP4 receptor antagonists should have promising potential for tumor immunotherapy. Aiming at improving the drug-like properties, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives were designed and synthesized through a scaffold hopping strategy. The most promising compound 47 exhibited good EP4 antagonistic activity and excellent subtype selectivity, as well as favorable drug-like properties. It effectively suppressed the expression of multiple immunosuppression-related genes in macrophages. Meanwhile, oral administration of compound 47, alone or in combination with anti-PD-1 antibody, significantly enhanced the antitumor immune response and inhibited tumor growth in the mouse CT26 colon carcinoma model.

Discovery of novel Thieno[2,3-d]imidazole derivatives as agonists of human STING for antitumor immunotherapy using systemic administration

The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC50 value of 1.2 nM. Compound 45 was found to bind to multiple human STING isoforms and accordingly activated the downstream TBK1/IRF3 and NF-κB signaling pathways in the reporter cells bearing with different STING isoforms. The activation on STING signaling pathway was abolished in the STING knock-out cells, indicating that it is a specific STING agonist. Compound 45 significantly inhibited the tumor growth in allograft 4T1 and CT26 tumor models by systemic administration, and more significantly, 45 was able to induce tumor regression in CT26 tumor model without inducing weight loss, suggesting that compound 45 is a highly promising candidate worthy for further development.

3D-QSAR and scaffold hopping based designing of benzo[d]ox-azol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2(3H)-one derivatives as selective aldehyde dehydrogenase 1A1 inhibitors: Synthesis and biological evaluation.

Aldehyde dehydrogenase 1 (ALDH1A1), an oxidoreductase class of enzymes, is overexpressed in various types of cancer cell lines and is the major cause of resistance to the Food and Drug Administration (FDA)-approved drug, cyclophosphamide (CP). In cancer conditions, CP undergoes a sequence of biotransformations to form an active metabolite, aldophosphamide, which further biotransforms to its putative cytotoxic metabolite, phosphoramide mustard. However, in resistant cancer conditions, aldophosphamide is converted into its inactive metabolite, carboxyphosphamide, via oxidation with ALDH1A1. Herein, to address the issue of ALDH1A1 mediated CP resistance, we report a series of benzo[d]oxazol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2(3H)-one derivatives as selective ALDH1A1 inhibitors. These inhibitors were designed using a validated 3D-quantitative structure activity relationship (3D-QSAR) model coupled with scaffold hopping. The 3D-QSAR model was developed using reported indole-2,3-diones based ALDH1A1 inhibitors, which provided field points in terms of electrostatic, van der Waals and hydrophobic potentials required for selectively inhibiting ALDH1A1. The most selective indole-2,3-diones-based compound, that is, cmp 3, was further considered for scaffold hopping. Two top-ranked bioisosteres, that is, benzo[d]oxazol-2(3H)-one and 2-oxazolo[4,5-b]pyridin-2(3H)-one, were selected for designing new inhibitors by considering the field pattern of 3D-QSAR. All designed molecules were mapped perfectly on the 3D-QSAR model and found to be predictive with good inhibitory potency (pIC50 range: 7.5-6.8). Molecular docking was carried out for each designed molecule to identify key interactions that are required for ALDH1A1 inhibition and to authenticate the 3D-QSAR result. The top five inhibitor-ALDH1A1 complexes were also submitted for molecular dynamics simulations to access their stability. In vitro enzyme assays of 21 compounds suggested that these compounds are selective towardALDH1A1 over the other two isoforms, that is,ALDH2 and ALDH3A1. All the compounds were found to be at least three and two times more selective towardALDH1A1 over ALDH2 and ALDH3A1, respectively. All the compounds showed an IC50 value in the range of 0.02-0.80 μM, which indicates the potential for these to be developed as adjuvant therapy for CP resistance.

Tetrahydropyridin-4-ylpicolinoylglycines as novel and orally active prolyl hydroxylase 2 (PHD2) inhibitors for the treatment of renal anemia

Prolyl hydroxylase 2 (PHD2) is a key regulatory enzyme responsible for the degradation of hypoxia-inducible factor-α (HIF-α). Pharmacological inhibition of PHD2 stabilizes HIF-α and induces the production of endogenous erythropoietin (EPO), which is regarded as a promising strategy for the treatment of renal anemia. To date, a series of PHD2 inhibitors have been approved or advanced into clinical studies. In this study, we developed a new type of PHD2 inhibitors with the tetrahydropyridin-4-ylpicolinoylglycine scaffold by using a scaffold hopping strategy. Among them, compound 25 showed potent inhibition toward PHD2 with an IC50 of 6.55 ± 0.41 nM. Furthermore, compound 25 upregulated reticulocytes in C57BL/6 mice. The subacute toxicological assay demonstrated 25 has no obvious toxicity in vivo. Overall, compound 25 is a promising candidate for the treatment of renal anemia.