Binding Mode Analysis Research Articles

Novel Insecticidal Benzo[4,5]imidazo[1,2-b]pyrazole Derivatives Identified through Ring-Closure Scaffold Hopping on Fipronil.

A series of innovative benzo[4,5]imidazo[1,2-b]pyrazole scaffold containing compounds were rationally designed through a ring-closure scaffold hopping strategy and synthetized with an intermediate derivatization approach. Physicochemical properties analysis indicated the potential pesticide-likeness of the target compounds. The optimal target compound A14 showed relatively good insecticidal activity against P. xylostella, with an LC50 value of 37.58 mg/L, and demonstrated lower acute fish toxicity compared to fipronil. Docking binding mode analysis demonstrated that compound A14 bound to GABAR through a H-bond between the amide group and the residue of 6'Thr. The differences in binding modes between benzo[4,5]imidazo[1,2-b]pyrazole target compounds and fipronil may be a key factor for the reduced insecticidal activities. The elucidated binding mode and SAR profile lay a foundation for the further structural optimization of insecticidal benzo[4,5]imidazo[1,2-b]pyrazole derivatives.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Tribromo-substituted Imidazole Analogs

IntroductionWith the increasing rate of antimicrobial resistance, there is an urgent demand of developing newer antimicrobial agents. In the present study we report a novel series of eighteen 1-(aryl)-2-(2,4,5-tribromo-1H-imidazol-1-yl)ethan-1-ones, which were synthesized and their spectral characterization was performed. The in-vitro studies of the compounds were carried out. Molecular modeling studies were performed on the most promising compound. The results obtained would help develop new compounds that may have broad-spectrum therapeutic effects. MethodsThe compounds were synthesized by reacting the corresponding bromo-imidazoles with substituted phenacyl bromides. The predictive ADME studies, MM-GBSA studies, and In-vitro studies were carried out for all the compounds. Binding mode analysis of the most active compounds was carried out. DFT investigations were also performed. Results and discussionsAll the synthesized compounds were found to be active against the different strains of microorganisms used in the in-vitro analysis. Binding mode analysis of the most active compounds were carried out in the active site of glucosamine-6-phosphate synthase (2VF5) and crystal structure of Mycobacterium tuberculosis InhA inhibited by PT70 (2X22). With the increasing global challenge of multi-drug resistance and the urgent need for new antimicrobial agents, these compounds show promising potential to meet emerging therapeutic demands in treating infectious diseases.

Insecticide binding mode analysis and biological effects of acetylcholinesterase target-site resistance mutations in Spodoptera frugiperda

It is urgent to solve insecticide resistance issues for fall armyworm (FAW), Spodoptera frugiperda. Some acetylcholinesterase-1 (Ace-1) mutations (A201S, G227A and F290V) have been identified as a cause of FAW resistance to organophosphates (OPs) and carbamates insecticides (CXs). However, the structural biological mechanisms on the relationship between the Ace-1 mutations and resistance to OPs and CXs still remain elusive. In this study, the A201S and F290V mutaions were found in eight fields populations of FAW except the G227A. Molecular docking revealed that the four Ace-1 proteins (Ace1-WT, Ace1-A201S, Ace1-G227A and Ace1-F290V) had the same binding modes and the same binding energies with acetylcholine (Ach), trichlorfon, chlorpyrifos, methomyl, carbaryl and chlorpyrifos oxide. The structural biological analysis revealed that the A201S mutations can enhance enzyme catalytic efficiency by introducing the hydroxyl group (-OH) from serine which performed the same function as the main-chain -NH and enhanced the interaction with the carboxy oxygen of acetylcholine (Ach), and the F290V mutation can effectively improve FAW resistance to insecticides by increasing the likelihood of Ach to enter the enzyme's active center for phenylalanine replaced by smaller valine under insecticide inhibition conditions. The bioassays and age-stage-specific life table analysis of FAW-SS and FAW-F290V populations revealed that F290V mutation effectively contributed to FAW resistance with a low fitness cost. This study provides a theoretical basis for future pest resistance management.

Rational Design and Synthesis of Novel Benzimidazole Derivatives as Potential β-Glucosidase Inhibitors

Background: β-Glucosidase has a variety of biological functions. A structural model for a potential β-glucosidase inhibitor has been proposed in the previous studies. Objective: A series f new diaryl derivatives linked through benzimidazole have been randomly and rationally designed, synthesized, and evaluated for their inhibitory activities against β-glucosidase (almond). The proposed structural model provides a new strategy for the design of potent β-glucosidase inhibitors. Methods: According to the model, a series of benzimidazole derivatives were designed and synthesized, and their inhibitory activity, Ki value, inhibitory type, and binding mode analysis (PDB ID: 2J7C) on β-glucosidase (almond) were evaluated. Results: Two compounds 7b and 7d were the best inhibitors with IC50 values of 7.86 M and 3.52 μM, respectively. Their Ki values were calculated to be 9.91 μM and 5.81 μM, respectively. Conclusion: The SAR analysis suggested that such benzimidazole derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds on o-trihydroxyphenol; the additional phenyl ring on the other side towards the solvent-exposed region played a very important role in improving their inhibitory activity against β-glucosidase

Pinpointing prime structural attributes of potential MMP-2 inhibitors comprising alkyl/arylsulfonyl pyrrolidine scaffold: a ligand-based molecular modelling approach validated by molecular dynamics simulation analysis

ABSTRACT MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1′ pocket of MMP-2 similar to ‘a basketball passing through a hoop’ allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2′ pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.

Synthesis, biological screening, and binding mode analysis of some N-substituted tetrahydroquinoline analogs as apoptosis inducers and anticancer agents

One of the most common malignancies in the world is lung cancer. Lung cancer involves mutations in many different genes, however, EGFR, KRAS, PTEN, and PIK3CA involvement is more frequent. The lack of effective drugs and drug resistance are major issues and obstacles associated with the current treatment of lung cancer. Seven novel tetrahydroquinoline analogs were synthesized and screened against a range of cancer cell lines in this study. Among these, 17f (IC50=0.082 µM) was shown to be the most potent when compared to the standard drug 5-Flurouracil (5FU) (IC50=0.28 µM). Moreover, flow cytometry analysis was carried out to ascertain the nature of programmed cell death. This provides conclusive evidence of late apoptosis in all synthesized compounds when contrasted with the standard drug (5FU) and control. After comparing all of the outputs, additional binding mode analysis was carried out to determine the potential mechanism of its anticancer activity. Molecular docking and MD simulation studies were carried out, and the results show that all of the synthesized compounds 17-a-f (17f docking score -10.5 Kcal/mol) have a better binding affinity towards mTOR (PDB id: 4JT6) than both the standard drug 5FU and the co-crystal ligand X6K (docking score: -7.6 Kcal/mol). Despite the aforementioned information, strong hit compounds from this series may eventually be developed to become lead mTOR inhibitors for the treatment of lung cancer.

Computational Modeling Oriented Substructure Splicing Application in the Identification of Thiazolidine Derivatives as Potential Low Honeybee Toxic Neonicotinoids.

With the aim of identifying novel neonicotinoid insecticides with low bee toxicity, a series of compounds bearing thiazolidine moiety, which has been shown to be low bee toxic, were rationally designed through substructure splicing strategy and evaluated insecticidal activities. The optimal compounds A24 and A29 exhibited LC50 values of 30.01 and 17.08 mg/L against Aphis craccivora, respectively. Electrophysiological studies performed on Xenopus oocytes indicated that compound A29 acted on insect nAChR, with EC50 value of 50.11 μM. Docking binding mode analysis demonstrated that A29 bound to Lymnaea stagnalis acetylcholine binding protein through H-bonds with the residues of D_Arg55, D_Leu102, and D_Val114. Quantum mechanics calculation showed that A29 had a higher highest occupied molecular orbit (HOMO) energy and lower vertical ionization potential (IP) value compared to the high bee toxic imidacloprid, showing potentially low bee toxicity. Bee toxicity predictive model also indicated that A29 was nontoxic to honeybees. Our present work identified an innovative insecticidal scaffold and might facilitate the further exploration of low bee toxic neonicotinoid insecticides.

Analysis of Binding Modes between Three Perfluorosulfonates and GPER Based on Computational Simulation and Multiple Spectral Methods.

Perfluorinated compounds (PFCs) belong to a significant category of global environmental pollutants. Investigating the toxicological effects of PFCs within biological systems is of critical significance in various disciplines such as life sciences, environmental science, chemistry, and ecotoxicology. In this study, under simulated human physiological conditions (pH = 7.4), a combination of multiple spectroscopic techniques and computational simulations was employed to investigate the impact of perfluorinated compounds (PFCs) on the G protein-coupled estrogen receptor (GPER). Additionally, the research focused on exploring the binding modes and toxicological mechanisms between PFCs and GPER at the molecular level. All three perfluorinated sulfonic acids (PFSAs) can induce quenching of GPER fluorescence through static quenching and non-radiative energy transfer. Steady-state fluorescence calculations at different temperatures revealed apparent binding constants in the order of 106, confirming a strong binding affinity between the three PFSAs and GPER. Molecular docking studies indicated that the binding sites of PFSAs are located within the largest hydrophobic cavity in the head region of GPER, where they can engage in hydrogen bonding and hydrophobic interactions with amino acid residues within the cavity. Fourier transform infrared spectroscopy, three-dimensional fluorescence, and molecular dynamics simulations collectively indicate that proteins become more stable upon binding with small molecules. There is an overall increase in hydrophobicity, and alterations in the secondary structure of the protein are observed. This study deepens the comprehension of the effects of PFCs on the endocrine system, aiding in evaluating their potential impact on human health. It provides a basis for policy-making and environmental management while also offering insights for developing new pollution monitoring methods and drug therapies.

Screening of Polyphenolic compounds to identify dual inhibitors against Glycogen Synthase 3β and Acetylcholinesterase for the treatment of Alzheimer’s Diseases

Alzheimer’s diseases is a neurodegenerative progressive diseases accompanied by complex pathology. Because of its complex pathology, multi-target ligands are considered as an attractive strategy for new drug development against AD. In this context dual inhibition of AChE and GSK-3β can be considered as an important strategy. In this work, various polyphenolic compounds from the literature were collected and evaluated against AChE and GSK-3β using molecular docking. The results indicated good binding potential of all the docked compounds for GSK-3β (9kcal/mol), while weak to good binding potential for AChE (8 to 12kcal/mol). The binding mode analysis of GSK-3 docked complexes showed interactions with key residues like Asp133 and Val135 which are important for molecular recognition. Additionally, the docked compounds showed interactions with Leu132, Arg141 and Cys199, the residues important for potency and selectivity. With respect to AChE, the compounds mostly occupied peripheral aromatic site in the active site of AChE, the site important for binding of ligands and inhibitor. The binding mode analysis showed interactions with key residues Tyr124, Ser293 and Arg296 important for substrate binding and recognition. Further the polar interactions were also noted for His447 and Ser203 (residues important for Ach hydrolysis) in some of the identified ligands. Overall the work resulted in the identification of eight compounds 5'-geranyl-5,7,2',4'tetrahydroxyflavone-2, Kuwanon E 4, Gossypetin, Kaempferide, Galangin, Kaempferol, baicalein and Ellagic acid with the potential dual inhibition of AChE and GSK-3β. It should be noted that kaempferide was not reported in the literature for AChE inhibition, while except baicalein none of the compounds were reported for GSK-3β. Further, the eight identified compounds were subjected for ADME profiling using SwissADME which showed their drug like character. Therefore, based on the results from this study, the above mentioned eight compounds can be looked upon with the potential of dual inhibition against AChE and GSK-3β.

Exploring the Anticancer Potential of Semisynthetic Derivatives of 7α-Acetoxy-6β-hydroxyroyleanone from Plectranthus sp.: An In Silico Approach.

The diterpene 7α-acetoxy-6β-hydroxyroyleanone isolated from Plectranthus grandidentatus demonstrates promising antibacterial, anti-inflammatory and anticancer properties. However, its bioactivity may be enhanced via strategic structural modifications of such natural products through semisynthesis. The anticancer potential of 7α-acetoxy-6β-hydroxyroyleanone and five derivatives was analyzed in silico via the prediction of chemicals absorption, distribution, metabolism, excretion, and toxicity (ADMET), quantum mechanical calculations, molecular docking and molecular dynamic simulation. The protein targets included regulators of apoptosis and cell proliferation. Additionally, network pharmacology was used to identify potential targets and signaling pathways. Derivatives 7α-acetoxy-6β-hydroxy-12-O-(2-fluoryl)royleanone and 7α-acetoxy-6β-(4-fluoro)benzoxy-12-O-(4-fluoro)benzoylroyleanone achieved high predicted binding affinities towards their respective protein panels, with stable molecular dynamics trajectories. Both compounds demonstrated favorable ADMET parameters and toxicity profiles. Their stability and reactivity were confirmed via geometry optimization. Network analysis revealed their involvement in cancer-related pathways. Our findings justify the inclusion of 7α-acetoxy-6β-hydroxy-12-O-(2-fluoryl)royleanone and 7α-acetoxy-6β-(4-fluoro)benzoxy-12-O-(4-fluoro)benzoylroyleanone in in vitro analyses as prospective anticancer agents. Our binding mode analysis and stability simulations indicate their potential as selective inhibitors. The data will guide studies into their structure optimization, enhancing efficacy and drug-likeness.

Abstract 1808: Discovery of highly selective novel MTA-cooperative PRMT5 inhibitors for the treatment of cancers

Abstract Protein arginine methyltransferase 5 (PRMT5), a type II PRMT catalyzing the formation of symmetric dimethylation of arginine residues on histone and non-histone proteins, regulates many biological pathways in mammalian cells, including cell growth and differentiation. Methylthioadenosine phosphorylase (MTAP) is required for the methionine salvage pathway, deletion of MTAP leads to the accumulation of inhibitory PRMT5 cofactor methylthioadenosine (MTA). MTAP gene is adjacent to and frequently co-deleted with CDKN2A gene, the most commonly deleted tumor suppressor gene in human cancers. The increase in MTA significantly reduced PRMT5 activity in MTAP-deficient cancer cells, rendering them more vulnerable to PRMT5 inhibition than normal cells. Selective Inhibitors of PRMT5-MTA complex (MTA-cooperative) are supposed to exhibit an increased therapeutic index compared to first generation PRMT5 inhibitors for the treatment of MTAP-deleted (MTAP-del) cancer patients. Guided by computation-aided drug design (CADD), binding mode analysis of known PRMT5 inhibitors has led to the design and synthesis of a novel series of MTA-cooperative PRMT5 inhibitors. Many compounds within this series were found to inhibit PRMT5/MEP50 complex with single digit nM of IC50 in enzymatic assay. Cell based activity of these compounds was assessed by measuring the symmetric demethylarginine (SDMA) and 10-day cell proliferation assays. Several compounds exhibited low double-digit nM of cellular potency in HCT116 MTAP-del cells, the inhibition of SDMA and anti-proliferation activities in HCT116 MTAP-del cells over HCT116 MTAP-WT cells have excellent selectivity (80 - 400 fold). Further optimization of in vitro and in vivo pharmacokinetic properties has yielded candidate compounds suitable for evaluation of pharmacodynamic effect in the LU99 MTAP-del NSCLC xenograft model. Tumor growth inhibition (TGI) was observed in a dose-dependent manner, accompanied by a reduction of PRMT5-mediated SDMA levels in both the tumor and bone marrow. In summary, we have identified compounds with novel scaffolds that are potent and highly selective MTA-cooperative PRMT5 inhibitors. Further development of the second-generation PRMT5 inhibitors for treatment of cancers is also planned. Citation Format: Wen-Lian Wu, Taishan Hu, Zhilin Deng, Honghai Li, Quanrong Shen, Lei Zhang, Xiaochu Ma, Peihua Sun, Cindy Cheng, Fang Liu, Xin Chen, Ye Hua, Bryan Huang. Discovery of highly selective novel MTA-cooperative PRMT5 inhibitors for the treatment of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1808.

Targeting human progesterone receptor (PR), through pharmacophore-based screening and molecular simulation revealed potent inhibitors against breast cancer

Breast cancer, the prevailing malignant tumor among women, is linked to progesterone and its receptor (PR) in both tumorigenesis and treatment responsiveness. Despite thorough investigation, the precise molecular mechanisms of progesterone in breast cancer remain unclear. The human progesterone receptor (PR) serves as an essential therapeutic target for breast cancer treatment, warranting the rapid design of small molecule therapeutics that can effectively inhibit HPR. By employing cutting-edge computational techniques like molecular screening, simulation, and free energy calculation, the process of identifying potential lead molecules from natural products has been significantly expedited. In this study, we employed pharmacophore-based virtual screening and molecular simulations to identify natural product-based inhibitors of human progesterone receptor (PR) in breast cancer treatment. High-throughput molecular screening of traditional Chinese medicine (TCM) and zinc databases was performed, leading to the identification of potential lead compounds. The analysis of binding modes for the top five compounds from both database provides valuable structural insights into the inhibition of HPR for breast cancer treatment. The top five hits exhibited enhanced stability and compactness compared to the reference compound. In conclusion, our study provides valuable insights for identifying and refining lead compounds as HPR inhibitors.

Discovery of small molecule entry inhibitors targeting the linoleic acid binding pocket of SARS-CoV-2 spike protein

Spike glycoprotein has a significant role in the entry of SARS-CoV-2 to host cells, which makes it a potential drug target. Continued accumulation of non-synonymous mutations in the receptor binding domain of spike protein poses great challenges in identifying antiviral drugs targeting this protein. This study aims to identify potential entry inhibitors of SARS-CoV-2 using virtual screening and molecular dynamics (MD) simulations from three distinct chemical libraries including Pandemic Response Box, Drugbank and DrugCentral, comprising 6971 small molecules. The molecules were screened against a binding pocket identified in the receptor-binding domain (RBD) region of the spike protein which is known as the linoleic acid binding pocket, a highly conserved motif among several SARS-CoV-2 variants. Through virtual screening and binding free energy calculations, we identified four top-scoring compounds, MMV1579787 ([2-Oxo-2-[2-(3-phenoxyphenyl)ethylamino]ethyl]phosphonic acid), Tretinoin, MMV1633963 ((2E,4E)-5-[3-(3,5-dichlorophenoxy)phenyl]penta-2,4-dienoic acid) and Polydatin, which were previously reported to have antibacterial, antifungal or antiviral properties. These molecules showed stable binding on MD simulations over 100 ns and maintained stable interactions with TYR365, PHE338, PHE342, PHE377, TYR369, PHE374 and LEU368 of the spike protein RBD that are found to be conserved among SARS-CoV-2 variants. Our findings were further validated with free energy landscape, principal component analysis and dynamic cross-correlation analysis. Our in silico analysis of binding mode and MD simulation analyses suggest that the identified compounds may impede viral entrance by interacting with the linoleic acid binding site of the spike protein of SARS-CoV-2 regardless of its variants, and they thus demand for further in vitro and in vivo research. Communicated by Ramaswamy H. Sarma

Design, Synthesis, and in-silico Studies of New Disubstituted Benzimidazoles: Evaluation of In-vitro Anticancer and Antimicrobial Activity

A series of thirteen new benzimidazole scaffolds 4(a-m) was synthesized by nucleophilic substitution of 2-chloro- N-(aryl)-acetamides 3(a-m) with 2-(substituted phenyl)-1H-benzo[d]imidazoles 2(a-e) in N.N-Dimethylformamide. All the synthesized compounds were tested on the MCF-7 cell line, followed by antibacterial and antifungal activity. The anticancer activity was determined using MTT assay technique, whereas the antimicrobial activity was carried out using two-fold serial dilution technique. Among all the tested compounds, compound 4b exhibited the highest anticancer and antimicrobial activity, comparable to the standard drug. Finally, the binding mode analysis of the highly active compounds was performed at the active binding sites of the co-crystallized structure of the MCF-7 cell line (PDB ID 1ZXM) and glucosamine-6-phosphate synthase (PDB ID 2VF5). In silico absorption, distribution, metabolism, and excretion studies were also carried out.. KEYWORDS :Benzimidazoles, Cytotoxicity, in silico studies, MCF-7 cell lines, MTT assay.

Computational Analysis of Lenalidomide and Pomalidomide Enantiomers' Binding Interactions With Prostaglandin (PG)-Protein: Implications for Inflammatory Activity in Cancer.

Lenalidomide and Pomalidomide are chiral immunomodulatory drugs (IMiDs) and have antiangiogenic and anti-immunomodulatory activity. Each enantiomer may have distinct binding and biological activity. This study aimed to explore the in-silico binding of both enantiomers of Lenalidomide and Pomalidomide with Prostaglandin and its potential impact on persisting inflammatory activity in cancer. This can further provide insight into the transport of pro-inflammatory mediators and their potential implications for the inflammatory microenvironment within tumors. Molecular docking studies were performed to explore the binding potential of both enantiomers of Lenalidomide and Pomalidomide with Pg protein. The crystal structure of Pg-protein (PDB ID: 1IW7) was obtained from the Protein Data Bank. The binding energies for (-)-Lenalidomide and (+)-Lenalidomide were -6.7 and -7.2 kcal/mol, respectively, while the binding energies for (-)-Pomalidomide and (+)-Pomalidomide were -7.8 and -8.1 kcal/mol, respectively. The binding mode analysis revealed that all four compounds formed hydrogen bonds with key amino acid residues of Pg-protein. The hydrogen bond distances for (-)-Lenalidomide, (+)-Lenalidomide, (-)-Pomalidomide, and (+)-Pomalidomide were 2.1 Å, 2.0 Å, 2.2 Å, and 2.1 Å, respectively. The present study suggests that both enantiomers of Lenalidomide and Pomalidomide have a high affinity for Pg-protein and can effectively target the Pg-protein pathway to persist inflammatory activity in cancer.By targeting inflammation-mediated processes, these drugs may offer a novel strategy to combat tumor progression.

Exploration of bromodomain ligand-linker conjugation sites for efficient CBP/p300 heterobifunctional degrader activity

Synthesis of proteolysis targeting chimeras (PROTACs) involves conjugation of an E3 ligase binding ligand to a ligand targeting a protein of interest via a rigid or flexible chemical linker. The choice of linker conjugation site on these ligands can be informed by structural analysis of ligand-target binding modes, the feasibility of synthetic procedures to access specific sites, and computational modeling of predicted ternary complex formations. Small molecules that target bromodomains - epigenetic readers of lysine acetylation - typically offer several potential options for linker conjugation sites. Here we describe how varying the linker attachment site (exit vector) on a CBP/p300 bromodomain ligand along with linker length affects PROTAC degradation activity and ternary complex formation. Using kinetic live cell assays of endogenous CBP and p300 protein abundance and bead-based proximity assays for ternary complexes, we describe the structure-activity relationships of a diverse library of CBP/p300 degraders (dCBPs).

Inhibition of Bungarus caeruleus snake venom toxicity by Citrus reticulata methanolic extract and in-silico analysis of possible binding modes

Inhibition of Bungarus caeruleus snake venom toxicity by Citrus reticulata methanolic extract and in-silico analysis of possible binding modes

Novel scaffolds identification against Mpro of SARS-CoV-2 using shape based screening and molecular simulation methods

BackgroundPfizer in the USA has pioneered an orally active drug called Nirmatrelvir (PF-07321332) targeting the main protease (Mpro) protein of SARS-CoV-2. However, the current scenario demands additional scaffolds with greater potency and binding affinity. MethodsVarious computational techniques were employed to detect the new scaffold in comparison to Mpro. These techniques included shape-based screening, molecular docking, molecular dynamic simulation (MDS), and ADMET studies. The query molecule for the shape-based screening in the ZINC database was PF-07321332. In docking investigations, every screened molecule was assessed for binding mode analysis. The binding strength of the top 10 screened compounds was further examined using the Prime/MMGBSA, Glimpse, and KDeep tools. Only best four of the screened molecules were chosen for stability assessments within Mpro's active site using Gromacs for MDS studies. To validate the Gromacs MDS results, all of these screened molecules were subsequently processed in Desmond software for triplicate MDS investigations (per complex). Significant findingsThrough analysis involving RMSD, RMSF, H-bonding, and the radius of gyration, it was observed that during both MDS studies, the molecules ZINC000073548482, ZINC000036121206, and ZINC000064468475 displayed minimal fluctuations while exhibiting higher binding free energy against Mpro. This suggests that these molecules showcased exceptional stability within Mpro's active site throughout both MDS processes when compared to the reference (6W63). Consequently, these chemically varied screened molecules (ZINC000073548482, ZINC000036121206, and ZINC000064468475) could potentially serve as novel, diverse shape similar scaffolds against Mpro, previously unreported against SARS-CoV-2. However, these claims require experimental validation. The multiple screening methods with both MDS tools found valuable to find the novel scaffolds against Mpro. These scaffolds hold promise for furthering the development of innovative and refined therapeutics targeting Mpro in SARS-CoV-2.

Discovery of a novel ROCK2 ATP competitive inhibitor by DNA-encoded library selection

Neurodegeneration disorders, such as Alzheimer's disease (AD), have garnered significant attention due to their impact on individuals and society as a whole. Understanding the mechanisms behind these disorders and developing effective therapy strategies is of utmost importance. One potential therapeutic target that has emerged is Rho-associated coiled-coil containing protein kinase 2 (ROCK2), as its accumulation and activity have been closely linked to memory loss. In this report, we present the findings of a recent discovery involving a new molecule that has the ability to competitively inhibit ROCK2 activity. This molecule was identified through the utilization of a DNA-encoded library (DEL) screening platform. Following selection against ROCK2, an off-DNA compound was synthesized and examined to ascertain its inhibitory properties, selectivity, mechanism of action, and binding mode analysis. From the screening, compound CH-2 has demonstrated an IC50 value of 28 nM against ROCK2, while exhibiting a 5-fold selectivity over ROCK1. Further analysis through molecular docking has provided insights into the specific binding modes of this compound. Our findings suggest that DEL selection offers a rapid method for identifying new inhibitors. Among these, the CH-2 compound shows promise as a potential ROCK2 inhibitor and warrants further investigation.

Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer’s disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood–brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein–ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.