MolDock Score Research Articles

In silico Structure-based Screening of Potential Anticancer Bioactive Natural Constituents from African Natural Products

Introduction: Inhibitors of topoisomerases, essential regulators of cancer development, are promising as cancer treatments. These enzymes regulate DNA topology and eliminate topological constraints during various biological processes, including replication, transcription, and recombination. Nature has continually offered scientists pathways to explore the development of new drugs. Indeed, since ancient times, various plant extracts have been utilized in treating multiple pathologies. Objective: It’s intriguing to diversify the therapeutic classes of natural topoisomerase 1 inhibitors. We aimed to explore the relationship between the toxicity of certain medicinal plants in North Africa and their anti-topoisomerase 1 enzyme activity. This investigation aims to discover potentially valuable compounds for fighting cancer by inhibiting the Topo1 enzyme, enriching the anticancer therapeutic class. Methods: This study has conducted a virtual screening of the African Natural Products Database to identify new scaffolds as topoisomerase 1 inhibitors. Molecular docking as a structure-based drug design approach was selected as one of the best approaches, and the complex code ID: 1K4T was used for this purpose. Results and Discussion: The molecular docking of more than 5790 natural products extracted from this database was docked into the binding site of the above-cited complex using the Modlock optimizer and Moldock score as search and scoring function algorithms, respectively. The top-ranked compounds have been assessed, analyzed, and compared to Topotecan and Irinotecan as reference ligands and drugs. Conclusion: Consequently, the seven natural products have shown a strong affinity to topoisomerase 1 and DNA. They establish a clear link between topoisomerase 1 inhibition and the anticancer activity of their corresponding plant extracts. Therefore, these hits are promising and serve as a base for further development of new topoisomerase 1 inhibitors.

In silico docking of anti-Alzheimer’s molecules from plant derivatives

Alzheimer’s disease is a progressive neurodegenerative disease and most often associated with memory deficits and cognitive decline. This study pertains to the development of plant based molecules that can help treating the Alzheimer’s conditions. Plant based molecules usually render no side effects, compared to the Allopathic drugs. Also, this study is based on the novel approach of Computer aided drug design. The molecules selected for study are screened for drug likeness property using DruLiTo software. The molecules are also screened for presence of carcinogenicity and mutagenicity using T.E.S.T software. The molecule is then docked with the receptor using the Molegro software. The best pose is selected and results are tabulated and concluded. Any molecule can be considered as ‘well-bound’ or ‘well-docked’ if it expresses a fairly negative docking score. The H-bond energy is also a parameter to be considered. Negative H-bond energy is correlated with strong H-bond interaction between the amino acid residues and the molecule. Out of the 3 compounds, Compound 1 [Punicic acid] docked with Acetylcholine Esterase Receptor[1ACJ] displayed the highest negative moldock score [-156.709] and is very well bound to the receptor, followed by compound 2 [Ferrulic acid] and compound 3[Caeffic acd]. These plant based molecules can be further tested to evaluate the extent of their anti-Alzheimer’s activity through pre-clinical and clinical testing and may also be incorporated in Ayurvedic medicine for treating Alzheimer’s disease.

Mechanistic investigation of quercetin in the management of diabetic foot ulcer by network pharmacology and molecular docking

BackgroundQuercetin (QUE), being a strong antioxidant, has been a part of Chinese traditional medicine for ages for the management of a large number of ailments including type 2 diabetes mellitus and its complications, primarily, Diabetic Foot Ulcer (DFU), but it is under lying mechanisms remain elusive. The introduction of network pharmacology and molecular docking has made it facile to investigate the mechanism of QUE-containing different plants and to validate the binding affinity of QUE with DFU protein respectively. AimThis study is aimed to investigate the mechanism of QUE in protecting against DFU through modern approaches viz. network pharmacology and molecular docking. Materials and methodsThe traditional Chinese medicine system pharmacology analysis platform (TCMSP) has been used to retrieve the active ingredients in various Chinese formulations. QUE was found to be a bioactive component of various Chinese formulations. The core therapeutic targets of QUE against DFU were identified using a protein–protein interaction (PPI) network. QUE-associated targets and genes related to DFU were obtained from different comprehensive databases (Pubchem, Swiss target prediction database, SEA database, String database, DisGeNET database, Molegro virtual docker version 6.0, ADMET lab2.0, SwissADME database) were intersected, and analyzed to obtain mapping targets and ranked to obtain key targets. ResultsThe Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway shows major pathways were obtained from for QUE was matrix metallopeptidase 9 (MMP9). Receptor-ligand interaction between QUE with MMP9 were evaluated via MVD 6.0 software. A total of 10 interactions of quercetin with the following moldock score, rerank score, and H-bond interactions were observed as -110.912, -37.33, and -12.11 respectively. Candidate targets MMP9 in diabetic complications were ascertained and found associated with QUE against the management of DFU. Molecular docking models showed that QUE could closely bind to the key targets MMP9 (PDB id: 2OVX). ADME/T Analysis is performed to check the pharmacokinetic and toxicity profile which complies with the ideal values. ConclusionsThis study proposed MMP9, as the key target of bioactive QUE in mechanistic control of DFU by lowering the activity of the IL-17 signalling pathway, Leukocyte trans-endothelial migration, Fluid shear stress, and atherosclerosis respectively. Future aspectsThe explication of mode of action of bioactive constituent QUE against DFU provide a theoretical basis for designing more promising agents further for treatment of DFU in diabetic patients.

Molecular docking, molecular dynamics, MM/PBSA approaches and bioactivity studies of nepetanudoside B isolated from endemic Nepeta aristata

Nepetanudoside B (NNB) was isolated from aerial parts of endemic Nepeta aristata crude extract (CH3OH-CHCl3) using silica gel (n-hexane, methanol, ethyl acetate, and dichlorometane, respectively) and sephadex LH-20 (65% Methanol-35% Chloroform) column chromatographies. Preparative-HPLC was used to purify NNB after activity-guided isolation of methanol sub-fractions with enzyme inhibitory and DNA protective properties. The NNB was determined using 1H,13C, COSY, HSQC, HMBC, and LC-MS/MS. The study compared the effects of NNB with conventional drugs in terms of its ability to inhibit enzymes such as urease, α-amylase, carbonic anhydrase (CA), lipase, α-glucosidase, and tyrosinase, as well as its ability to protect DNA. Enzyme kinetic and molecular docking were also used to evaluate this. NNB exhibited the best inhibitory activity on urease (1.28 ± 0.00 µg/mL), lipase (5.83 ± 0.10 µg/mL), BChE (3.73 ± 0.46 µg/mL), tyrosinase (7.39 ± 0.00 µg/mL), α-glucosidase (10.95 ± 0.00 µg/mL), α-amylase (22.11 ± 1.03 µg/mL) and AChE (25.68 ± 3.32 µg/mL), respectively. NNB has higher MolDock scores with binding energy in α-glucosidase (-233) and BChE (-8.90 kcal/mol). In enzyme kinetics studies, it was determined that urease, AChE, α-glucosidase, lipase, and CA were non-competitive , while BChE and tyrosinase were competitive inhibition mechanisms. Their Ki values were calculated as 0.09, 0.24, 0.09, 0.10, 0.08, 0.05, and 0.07 mM, respectively. Molecular dynamics simulation studies were performed for the interactions of NNB-BChE with MM/PBSA binding free energey RMSD, RMSF, Rg, SASA, and also the number of hydrogen bonds was calculated. The suitability and effectiveness of NNB have been proven in the food and pharmaceutical industries. The NNB molecule may lead to development studies as a BChE inhibitor. Communicated by Ramaswamy H. Sarma

Multi‐Technique Approach to Identify Potent Antimicrobial Agents from Calotropis procera: Insight into Pharmacophore Modeling, Molecular docking, MD simulation, and DFT Approaches

AbstractIn this research, natural compounds from Calotropisprocera were screened according to their antimicrobial activity against the pathogenic microbes selected as E. coli, S. aureus, Traypanosomabrucei, Moraxella catarrhalis, and Leishmaniaamazonensis. A 3D‐QSAR study was performed that evaluated the correlation of the structural parameters for the antimicrobial activity of the natural compounds which were selected based on their antimicrobial in‐vivo and in‐vitro studies previously. The screened active compounds were further studied by molecular docking to analyze the various interactions between the ligands and target proteins. Molecular docking was also performed with the three FDA‐approved antibiotics Cephalexin, Dicloxacillin, and Levofloxacin, having antimicrobial potential, and their results were compared with the docking results of the hit compounds. Results of ADME/T study of the compounds revealed that the two compounds stigmasterol and caryophyllene oxide are the hit compounds having no toxicity, best values of TPSA and average molecular weight. Validation of the docking results was also carried out by re‐docking as well as by molecular dynamic simulation. DFT study was also carried out to explore the stability and chemical properties of active compounds. Results showed that caryophyllene oxide is the hit compound because of the highest Moldock score with 3VOB protein, better than standard drugs and according to dynamic simulation analysis. Therefore, the derived results in these studies provide crucial information for designing antimicrobial drugs by using natural compounds that have better antimicrobial activity.

Exploring Citrus sinensis Phytochemicals as Potential Inhibitors for Breast Cancer Genes BRCA1 and BRCA2 Using Pharmacophore Modeling, Molecular Docking, MD Simulations, and DFT Analysis.

Structure-activity relationship (SAR) is considered to be an effective in silico approach when discovering potential antagonists for breast cancer due to gene mutation. Major challenges are faced by conventional SAR in predicting novel antagonists due to the discovery of diverse antagonistic compounds. Methodologyand Results: In predicting breast cancer antagonists, a multistep screening of phytochemicals isolated from the seeds of the Citrus sinensis plant was applied using feasible complementary methodologies. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed through the Flare project, in which conformational analysis, pharmacophore generation, and compound alignment were done. Ten hit compounds were obtained through the development of the 3D-QSAR model. For exploring the mechanism of action of active compounds against cocrystal inhibitors, molecular docking analysis was done through Molegro software (MVD) to identify lead compounds. Three new proteins, namely, 1T15, 3EU7, and 1T29, displayed the best Moldock scores. The quality of the docking study was assessed by a molecular dynamics simulation. Based on binding affinities to the receptor in the docking studies, three lead compounds (stigmasterol P8, epoxybergamottin P28, and nobiletin P29) were obtained, and they passed through absorption, distribution, metabolism, and excretion (ADME) studies via the SwissADME online service, which proved that P28 and P29 were the most active allosteric inhibitors with the lowest toxicity level against breast cancer. Then, density functional theory (DFT) studies were performed to measure the active compound's reactivity, hardness, and softness with the help of Gaussian 09 software. This multistep screening of phytochemicals revealed high-reliability antagonists of breast cancer by 3D-QSAR using flare, docking analysis, and DFT studies. The present study helps in providing a proper guideline for the development of novel inhibitors of BRCA1 and BRCA2.

In-silico design of novel 2-((4-chloro-6-methoxy-1H-indol-3-yl)thio)-N-(2-ethoxyphenyl)acetamide derivatives as potential inhibitors of influenza neuraminidase protein receptor

Influenza virus transmission is largely mediated by its mutation and genome reassortment from distinct strains resulting in drug-resistances and pandemics. This necessitates the need for the discovery of more potential influenza inhibitors to prevent future epidemics. An in-silico approach was utilized here to design six new (21a-f) potential inhibitors of influenza neuraminidase (NA) using a hit compound 21 with good binding affinity, predicted activity, and pharmacokinetic properties in our previous work. The modeled activities (pEC50) of the newly designed compounds (ranging between 8.188 and 7.600) were better than that of the hit compound 21 with predicted activity (pEC50) of 6.0101 and zanamivir (pEC50 of 5.6755) as the standard reference control used. The MolDock scores (ranging between −189.67 and −142.47 ​kcal/mol) of these newly designed compounds in the NA binding cavity were also better than the hit template 21 with a MolDock score of −125.33 ​kcal/mol and zanamivir standard drug (−136.36 ​kcal/mol). In addition, the conformational stability of the best-designed compound 21a in the NA binding cavity was further studied through the MD simulation of 100 ​ns. Moreover, the drug-likeness and ADMET predictions of these designed compounds showed their good oral bioavailability and pharmacokinetic profiling respectively. More so, the DFT calculations also revealed the relevance of these designed compounds in view of their smaller band energy gaps from the frontier molecular orbital calculations. This study could serve as a reliable in-silico perspective for the search and discovery of potential anti-influenza agents.

Molecular docking studies of some benzoxazole and benzothiazole derivatives as VEGFR-2 target inhibitors: In silico design, MD simulation, pharmacokinetics and DFT studies

Breast cancer, a deadly disease among women, demands effective interventions due to its global impact, with over one million annual cases. Current anti-breast cancer drugs displays several side effects, also most patients resists to these drugs during early treatment stage. Hence, global search for better drugs with less side effects became necessary. The objective of this study is to identify potential inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2), a critical target in breast cancer treatment. Molecular docking-based virtual screening of 45 benzoxazole/thiazole derivatives was conducted, followed by molecular dynamics simulations to explore ligand-protein interactions. Seven ligands (compounds 7, 10, 12, 13, 14, 20, and 26) demonstrated superior binding affinities ranging from −157.85 to −173.88 ​kcal/mol (MolDock scores) and −109.96 to −129.23 ​kcal/mol (Re-rank scores) compared to Sorafenib (−156.35 ​kcal/mol MolDock score and −102.63 ​kcal/mol Re-rank score). Compound 7, identified as a potential hit, exhibited stability in a 100-ns dynamic simulation. It was chosen as a template for designing novel inhibitors, resulting in five compounds with improved binding affinities ranging from −177.84 to −184.69 ​kcal/mol (MolDock scores) and −137.34 to −143.44 ​kcal/mol (Re-rank scores). Pharmacological profiling confirmed the drug-like properties of both the potential hit molecules and the designed compounds, with 0–1 violations against Lipinski's rule of five and favorable pharmacokinetics status. Density functional theory (DFT) studies illustrated the reactive nature of the designed compounds. These findings suggest the potential of these molecules as novel VEGFR-2 inhibitors for breast cancer treatment, providing promising prospects for future drug development.

Chemo-informatics applications in the design of novel 7-keto-sempervirol derivatives as SmCB1 inhibitors with potential for treatment of Schistosomiasis

The quest for a sound treatment on the vulnerable population suffering and dying as a result of the blood flukes, S. mansoni is on the increase because both Praziquantel and Oxamniquine widely used for the treatment of Schistosomiasis for over 51 years suffer resistance and recurrence. Here-in, chemo-informatics techniques such as QSAR modeling, pharmacokinetic, docking alongside MD simulation were harnessed in designing novel 7-keto- sempevirolsempevirol derivatives that are more competent against S. mansoni. Upon QSAR screening, compound 15, which appears to be in the model's acceptability space, emerges the best with a high predicted activity. 5 new analogues with improved activity against Schistosomiasis better than the standard drug PZQ were designed from compound 15 (template 15*) on an account of the descriptors significance from the model with robust and validated parameters. Also their pharmacokinetic profiles indicates that the designed compounds have the characteristics of a good drug. Furthermore, docking evaluation fulfilled ranges from −113.121 to −100.79 kcal/mol (moldock score), with compound U1 being the best (least moldock score of −113.121 compared to PZQ and 15* (template) having a moldock score value of (−87.21 and −83.37 kcal/mol). 100-ns MD Simulation on the U1-docked complex was run using Desmond 2019–4 package. The nature and steadiness of U1 compound within the enzyme active site was further confirmed by RMSD, RMSF, RoG and H-bond assessment. Hence, we recommend compound U1 targeting the SmCB1 enzyme (6YI7) for Schistosomiasis treatment and for further medicinal evaluation and utilization.

Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulation for the Discovery of Novel SARS-CoV-2 NSP3 Mac1 Domain Inhibitors.

Since the emergence of SARS-CoV-2, many genetic variations within its genome have been identified, but only a few mutations have been found in nonstructural proteins (NSPs). Among this class of viral proteins, NSP3 is a multidomain protein with 16 different domains, and its largest domain is known as the macrodomain or Mac1 domain. In this study, we present a virtual screening campaign in which we computationally evaluated the NCI anticancer library against the NSP3 Mac1 domain, using Molegro Virtual Docker. The top hits with the best MolDock and Re-Rank scores were selected. The physicochemical analysis and drug-like potential of the top hits were analyzed using the SwissADME data server. The binding stability and affinity of the top NSC compounds against the NSP3 Mac1 domain were analyzed using molecular dynamics (MD) simulation, using Desmond software, and their interaction energies were analyzed using the MM/GBSA method. In particular, by applying subsequent computational filters, we identified 10 compounds as possible NSP3 Mac1 domain inhibitors. Among them, after the assessment of binding energies (ΔGbind) on the whole MD trajectories, we identified the four most interesting compounds that acted as strong binders of the NSP3 Mac1 domain (NSC-358078, NSC-287067, NSC-123472, and NSC-142843), and, remarkably, it could be further characterized for developing innovative antivirals against SARS-CoV-2.

Molecular Docking of Combretastatin Derivatives to Combat Human Cancer Cells

Abstract Cancer is defined as the group of diseases which involve abnormal cell growth or controlled growth of abnormal cells that are present in any part of the body. The causative agents of cancer are chemical, environmental, viral, and mutagenic, which lead to the mutation of genes into oncogenes, which provoke or demean regulatory biochemicals, resulting in accelerated cellular growth. Combretastatin was selected as the candidate because it is a water-soluble prodrug which is quickly converted into combretastatin A4, a cancer-fighting substance. It has longer circulation, better drug targeting, increased efficiency, and fewer side effects. The research was carried out to find a potential drug that could inhibit the action of cancer in humans. In the experiment, 21 derivatives of combretastatin were subjected to molecular docking for analyzing the binding interactions of the derivative with the active site using the Protein Data Bank: 3DK9 through Molegro Virtual Docker 6.0. The docking showed that the (E)-1-(2,6-dimethoxypyridin-4-yl)-3-(1H-indol-3-yl)-2-methylprop-2-en-1-one was the most potent, had a Mol Dock score of-194.925 and gave interactions with Asp331, Gly31, and Thr57. Thus, this research can be further extended further to have more potent drugs.

Developmental landscape of computational techniques to explore the potential phytochemicals from Punica granatum peels for their antioxidant activity in Alzheimer's disease.

Alzheimer's disease (AD) is more commonly found in women than in men as the risk increases with age. Phytochemicals are screened in silico from Punica granatum peels for their antioxidant activity to be utilized for Alzheimer's disease. Alzheimer's disease is inhibited by the hormone estrogen, which protects the brain from the bad effects of amyloid beta and acetylcholine (ACh), and is important for memory processing. For the purpose, a library of about 1,000 compounds from P. granatum were prepared and studied by applying integrated computational calculations like 3D-QSAR, molecular docking, MD simulation, ADMET, and density functional theory (DFT). The 3D-QSAR model screened the active compounds B25, B29, B35, B40, B45, B46, B48, B61, and B66 by the field points and activity atlas model from the prepared library. At the molecular level, docking was performed on active compounds for leading hit compounds such as B25 and B35 that displayed a high MolDock score, efficacy, and compatibility with drug delivery against the antioxidant activity. Optimization of the structure and chemical reactivity parameter of the hit compound was calculated by DFT. Moreover, ADMET prediction was evaluated to check the bioavailability and toxicity of the hit compound. Hesperidin (B25) is found to be a hit compound after the whole study and can be synthesized for potent drug discovery in the future.

COMPARATIVE ANALYSIS OF SMALL MOLECULES AND NATURAL PLANT COMPOUNDS AS THERAPEUTIC INHIBITORS TARGETING RdRp AND NUCLEOCAPSID PROTEINS OF SARS COV 2: AN IN SILICO APPROACH

Objective: Coronavirus disease 2019 (COVID-19) is a virus-borne infection caused by the severe acute respiratory syndrome coronavirus disease-2 (SARS-CoV-2) virus. Nucleocapsid protein and RNA-dependent RNA polymerase (RdRp) activity in viral structural membrane, transcription, and replication have been identified as desirable targets for the development of novel antiviral strategies. The SARS-COV-2 N protein binds to the viral genome to promote the precise folding of the hammerhead ribozyme, preventing ineffective RNA confirmations, and directs them into a helical capsid shape or ribonucleoprotein complex, which is vital for viability. RNA synthesis requires RdRp to form phosphodiester bonds based on the RNA template. SARS-CoV-2 RNA synthesis, transcription, and replication depend on RdRp’s complex with nsp7 and nsp8. Methods: Our study targeted SARS-COV-2 RdRp and N proteins with natural plant compounds and small molecules. Hyperchem software optimized their structures geometrically and energetically. Based on MolDock, Rerank, and H-bonding energy, the best ligands were selected using the Molegro virtual docker. Results: In our analysis, we have identified nine compounds against N protein and seven compounds against RdRp protein that had more potent inhibitory effects with the lowest MolDock scores. The top 6 (Alpha solanine, Betanin, cairicoside I, Ginsenoside rb 1, Naringin, Polyphyllin I) compounds that have better inhibitory effects against both proteins. Conclusion: We conclude that the top six compounds have greater inhibitory efficacy against N and RdRp protein than other compounds. However, in vitro and in vivo experimental studies, as well as clinical trials, are required to achieve the desired result.

Melatonin and Vitamins as Protectors against the Reproductive Toxicity of Bisphenols: Which Is the Most Effective? A Systematic Review and Meta-Analysis.

Bisphenols such as bisphenol A (BPA), S (BPS), C (BPC), F (BPF), AF (BPAF), tetrabromobisphenol, nonylphenol, and octylphenol are plasticizers used worldwide to manufacture daily-use articles. Exposure to these compounds is related to many pathologies of public health importance, such as infertility. Using a protector compound against the reproductive toxicological effects of bisphenols is of scientific interest. Melatonin and vitamins have been tested, but the results are not conclusive. To this end, this systematic review and meta-analysis compared the response of reproductive variables to melatonin and vitamin administration as protectors against damage caused by bisphenols. We search for controlled studies of male rats exposed to bisphenols to induce alterations in reproduction, with at least one intervention group receiving melatonin or vitamins (B, C, or E). Also, molecular docking simulations were performed between the androgen (AR) and estrogen receptors (ER), melatonin, and vitamins. About 1234 records were initially found; finally, 13 studies were qualified for review and meta-analysis. Melatonin plus bisphenol improves sperm concentration and viability of sperm and increases testosterone serum levels compared with control groups; however, groups receiving vitamins plus bisphenols had lower sperm concentration, total testis weight, and testosterone serum levels than the control. In the docking analysis, vitamin E had the highest negative MolDock score, representing the best binding affinity with AR and ER, compared with other vitamins and melatonin in the docking. Our findings suggest that vitamins could act as an endocrine disruptor, and melatonin is most effective in protecting against the toxic effects of bisphenols.

Synthesis of New Zirconium (IV) Schiff-base Complexes: Spectral, Theoretical, and Molecular Docking Studies

Background: The development of the discipline of coordination chemistry owes a great deal to the use of Schiff-base metal chelates. Both Schiff base ligands and metal complexes are of interest due to their potential pharmacological effects. Schiff base derivatives have an extensive range of biological effects, including antitumor, antifungal, antibacterial, anticonvulsant, and antiviral properties. Objective: This study aimed to study the inorganic compound-based metallodrugs that have recently come into existence to provide an effective mechanism for medications that depend on the metal used and its characteristics. An effective platform for diverse pharmacological and therapeutic uses can be found in medicinal complex substances. Methods: The bi-molar reactions of zirconium tetrachloride with bidentate ligands were carried out in dry THF and were characterized by IR, UV-Visible, NMR and C, H, N, S analysis. The DFT method was used to investigate the molecular stability and bond strengths. Gaussian 09 and MolDock were used to optimise the geometry and to calculate the binding energy of all the complexes, respectively. Results: The analysis of the data revealed that the Schiff base, which has bivalent ligands (NS), was coordinated to zirconium via nitrogen and sulfur atoms. The optimum values for the structural parameters were calculated by density functional theory. Compound 5 showed the highest MolDock Score (-123.47 kcal/ mol) and H-bond interaction with active amino acids. Conclusion: The spectroscopic result indicates that the zirconium compounds were all non-electrolyte monomers with deformed octahedral structures. Compound 5 was shown to be the most active and effective of the bunch by both Gaussian software calculations and molecular docking study.

Anti-leishmanial, immunomodulatory and additive potential effect of Piperine on Leishmania major: The in silico and in vitro study of Piperine and its combination

BackgroundPiperine (Pn), an indole alkaloid compound found in pepper, is an effective compound with anti-leishmanial medications that administered alone or in combination. This study aimed to use Pn for possible biochemical targets and to assess mechanisms of anti-leishmanial action and immunomodulatory roles. MethodsThe ability of Pn to bind to interleukin-12P40 (IL-12P40) and interferon-γ (IFN-γ) was investigated using molecular docking. The leishmanicidal effect of Pn, meglumine antimoniate (Glucantime®; MA), and Pn plus MA was assessed on Leishmania major promastigotes and amastigotes. A real-time PCR was applied to quantify cytokines gene expression in drug-treated murine macrophages. ResultsThe molecular docking findings indicated that Pn could bind to IL-12P40/IFN-γ. In silico analyses showed an affinity of Pn to IL-12P40/IFN-γ, with the MolDock score of −236.91 and −64.87 kcal/mol, respectively. Pn plus MA reduced the proliferation rate of promastigote and amastigote forms of L. major compared to each drug alone (IC50 = 43.22 and 19.41 μg/mL, respectively). Moreover, the combination drug demonstrated no cytotoxicity as the selectivity index (SI) was 14.81. Also, Th1-related cytokines were upregulated, while Th2-related cytokines were downregulated in Pn combination-treated murine macrophages. ConclusionsThe superior effectiveness of combination therapy on L. major warrants further investigations on the clinical potential of this combination in the treatment of leishmaniasis.

Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide-Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors.

Inhibition of Pancreatic lipase (PL) is considered to be a promising target for the management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide-hydrazone analogs (5 aa-cm) were designed, synthesized and evaluated for their PL inhibitory potential. The analogs were designed using molecular modelling studies. The designed analogs were then synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the synthesized analogs showed PL inhibitory activity in the range of 4.13-48.35 μM, as compared with orlistat (0.86±0.09 μM). The most potent analog 5 bi (IC50 =4.13±0.95 μM) was found to show a competitive type of inhibition with Ki value of 0.725 μM. Additionally, the molecular docking study proved the binding of analog 5 bi at the active site of PL (PDB ID: 1LPB) with MolDock score of -141.279 kcal/mol. It also exhibited various interactions with the key amino acids namely Phe77, Phe215, Tyr114, Ser152, Arg256, His263, etc. Furthermore, the protein-ligand complex of analog 5 bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Å for the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide-hydrazone analogs in PL inhibition and further optimization could result in the generation of new leads as anti-obesity agents.

In silico Molecular Docking Study of Isatin and Acetophenone Derivatives as Antimicrobial Agent

The heterocyclic molecule isatin (1H-indole-2,3-dione) and its derivatives form a significant family of chemicals that can be employed as building blocks for the manufacture of pharmaceuticals. In the computational method known as docking, different software tools produce different positions at which ligands attach to their receptors. With the help of the Molegro virtual docker software (Version 6.0) and the PDB 3ACX, the present study attempts to perform a high-throughput in silico screening of 27 developed isatin and acetophenone-based derivatives. The docking results showed mol dock scores of -103.345 and one hydrogen bond interaction for the standard drug Ampicillin, on the other hand, the isatin and acetophenone-based derivatives YDA 27, YDA 26, YDA 25, YDA 17 and YDA 7 exhibited excellent mol dock scores and docking scores ranging from -104.23 to -121.126. Apart from the mol dock score, most of the studied compounds observed excellent hydrogen bonding with amino acids of PDB. Compound YDA 27, YDA 26, YDA 25, YDA 17 and YDA 7 showed 3 to 7 hydrogen bond interactions, however, the standard drug Ampicillin showed H-bond interaction with 1 amino acid Val 133 and Val 137. The results of the present study confirmed the significant antimicrobial potential of some designed isatin and acetophenone-based derivatives based on their mol dock values and other parameters when studied in silico, and the data obtained will give data that supports and provides perspectives in future research to develop an effective antimicrobial agent from these derivatives.

Chromone-3-acrylic acid ester analogues: Design, synthesis and biological evaluation as potential pancreatic lipase inhibitors

A novel series of 21 chromone-3-acrylic acid ester analogues (5aa-5cm) were designed, synthesized and evaluated for PL inhibitory activity. The molecular docking study indicate that all the designed chromone analogues have the good binding ability (MolDock score: -115.86 to -160.07 kcal/mol) in the active site of PL enzyme (PDB ID: 1LPB), showing interactions with essential amino acid residues (Phe77, Tyr114, Ser152, Phe215, Arg256). Also, all the analogues were checked for in silico drug likeness property and all were found to have drug like properties, obeying Lipinski rule of 5, with no PAINS alerts. Analogue 5am, with the best docking score, was stable in molecular dynamics simulation for 100 ns (maximum RMSD of 6.4 Å), showing crucial amino acid interactions for more than 60% of the simulation time. The structure of the synthesized analogues were then confirmed by NMR, HRMS and IR spectroscopy. Among the synthesized analogues, 5am and 5ad exhibited potent PL inhibition with IC50 of 5.16 ± 0.287 & 5.82 ± 0.933 µM, respectively, as compared with orlistat (IC50 = 0.86 ± 0.09 µM). The inhibition kinetics and in silico studies confirmed competitive type of inhibition of analogue 5am. The current work highlights the importance of chromone analogues as potential PL inhibitors. Further, the lead optimization may lead to much more potential PL inhibitors.

Structure-based drug design, molecular dynamics simulation, ADMET, and quantum chemical studies of some thiazolinones targeting influenza neuraminidase

The genetic mutability of the influenza virus leads to the existence of drug-resistant strains which is dangerous, particularly with the lingering coronavirus disease (COVID-19). This necessitated the need for the search and discovery of more potential anti-influenza agents to avert future outbreaks. In furtherance of our previous in-silico studies on 5-benzyl-4-thiazolinones as anti-influenza neuraminidase (NA) inhibitors, molecule 11 was selected as the template scaffold for the structure-based drug design due to its good binding, pharmacokinetic profiling, and better NA inhibitory activity. As such, eighteen (18) new molecules (11a-r) were designed with better MolDock scores as compared with the template scaffold and the zanamivir reference drug. However, the dynamic stability of molecule 11a in the binding cavity of the NA target (3TI5) showed water-mediated hydrogen and hydrophobic bondings with the active residues such as Arg118, Ile149, Arg152, Ile222, Trp403, and Ile427 after the MD simulation for 100 ns. The drug-likeness and ADMET assessment of all designed molecules predicted non-violation of the stipulated thresholds of Lipinski’s rule and good pharmacokinetic properties respectively. In addition, the quantum chemical calculations also suggested the significant chemical reactivity of molecules with their smaller band energy gap, high electrophilicity, high softness, and low hardness. The results obtained in this study proposed a reliable in-silico viewpoint for anti-influenza drug discovery and development.Communicated by Ramaswamy H. Sarma