In silico pharmacology最新文献

{"title":"Identification of bioactive compounds from <i>Vaccinium vitis-idaea</i> L. (Lingonberry) as inhibitors for treating KRAS-associated cancer: a computational approach.","authors":"Ayooluwa Ilesanmi,&nbsp;Gbenga Dairo,&nbsp;Sofela Salimat,&nbsp;Damilola S Bodun,&nbsp;Bibiire Awoyale,&nbsp;Toheeb A Balogun","doi":"10.1007/s40203-023-00165-1","DOIUrl":"https://doi.org/10.1007/s40203-023-00165-1","url":null,"abstract":"<p><p>Lung cancer is the cancer of the lung's epithelial cells typically characterized by difficulty breathing, chest pain, blood-stained coughs, headache, and weight loss. If left unmanaged, lung cancer can spread to other body parts. While several treatment methods exist for managing lung cancer, exploring natural plant sources for developing therapeutics offers great potential in complementing other treatment approaches. In this study, we evaluated the bioactive compounds in <i>Vaccinium vitis-idaea</i> for treating KRAS-associated lung cancer types. In this study, we concentrated on inhibiting the mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) by targeting an associated protein (Phosphodiesterase 6δ) to which KRAS form complexes. We evaluated bioactive compounds from Lingonberry (<i>Vaccinium vitis-idaea</i> L.), adopting computational approaches such as molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, and pharmacokinetics analysis. A total of 26 out of 39 bioactive compounds of <i>Vaccinium vitis-idaea</i> L. had a higher binding affinity to the target receptor than an approved drug, Sotorasib. Also, further analyses of all lead/top compounds in this study identified (+)-Catechin (Cianidanol), Arbutin, Resveratrol, and Sinapic acid, to be potential drug candidates that could be pursued. In sum, Arbutin, (+)-Catechin, and Sinapic acid are predicted to be the top compound of <i>Vaccinium vitis-idaea</i> L. because of their pharmacokinetic properties and drug-likeness attributes. Also, their stability to the target receptor makes them a potential drug candidate that could be explored for treating KRAS mutation-associated lung cancer.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-023-00165-1.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71430510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mechanistic assessment of the nature of pharmacodynamic drug-drug interaction in vivo and in vitro.","authors":"Kuteesa R Bisaso,&nbsp;Jackson K Mukonzo,&nbsp;Ene I Ette","doi":"10.1007/s40203-023-00168-y","DOIUrl":"https://doi.org/10.1007/s40203-023-00168-y","url":null,"abstract":"<p><p>Combination pharmacotherapy is becoming increasingly necessary because most diseases are pathophysiologically controlled at the subcellular level by target proteins in a combinatorial manner. We demonstrate the application of the stimulus-response mechanistic model in characterising the drug and physiological properties of pharmacodynamic drug-drug interactions (PDDI) using previously published in vitro and in vivo drug combination experiments. The in vitro experiment tested the effect of a combination of SCH66336 and 4-HPR on the survival of in squamous cell carcinoma cell lines, while the in vivo experiment tested the effect of a combination of cetuximab and cisplatin on tumour growth inhibition in female xenograft mice. The model adequately described both experiments, quantified both system and drug properties and predicted the nature of the PDDI mechanism. Strong baseline signals of 7.35 and 610 units existed in the in vitro and in vivo experiments respectively. An overall synergistic relationship (interaction index = 1.03E-8) was detected in the in vitro experiment. In the in vivo model, the overall interaction index was 70,139.45 implying an antagonistic interaction between the cisplatin and the cetuximab signals.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptidomimetics for CVD screened via TRADD-TRAF2 complex interface assessments.","authors":"A Manikandan,&nbsp;S Jeevitha,&nbsp;Laharika Vusa","doi":"10.1007/s40203-023-00166-0","DOIUrl":"https://doi.org/10.1007/s40203-023-00166-0","url":null,"abstract":"<p><p>The main aim of this study is to screen and develop Peptidomimetics to treat atherosclerosis (AS) which is a Cardio Vascular Disease (CVD). Peptidomimetics were obtained from the protein-protein interaction interface of TRADD (Tumor necrosis factor receptor type 1-associated DEATH domain protein) and TRAF2 (TNF receptor-associated factor 2) complex. TRADD-TRAF2 interaction is critical in AS pathogenesis since it assists a series of signal transducers that activate NF-κB. Conceptually, the triggered NF-κB makes an extensive amount of nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS), which boons the progress of AS. The examined TRADD-TRAF2 complex (PDB ID: 1F3V) and its interaction details revealed that the sequence range W11-G165 of TRADD highly interacts with TRAF2. The sequence range W11-G165 was selected for the design and preparation of the inhibitory peptide <i>in silico</i>. The selected sequence was mutated with the alanine scanning method to have a range of inhibitory peptides. With the help of different <i>in silico</i> tools, the top three, namely MIP11-25 L, MIP131-143 h, and MIP149-164 m peptides showed the best interaction with the critical residues of TRAF2. Thus, these three peptides were used for generating peptidomimetics using pepMMsMIMIC, a peptidomimetics virtual screening tool. Around 600 peptidomimetics were identified & and retrieved for further screening by employing molecular docking tools and MD (Molecular Dynamics) simulations. Density Functional Theory (DFT) and ADMET predictions were applied to validate the screened peptidomimetics druggability. In the results, peptidomimic compounds MMs03918858 and MMs03927281 with binding energy values of -9.6 kcal/mol and - 9.1 kcal/mol respectively were screened as the best and are proposed for further pre-clinical studies.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A network pharmacology approach to explore pharmacological mechanisms of <i>Asparagus racemosus</i> for ameliorative effect in epilepsy and comorbid progressive memory dysfunction.","authors":"Baldeep Kaur,&nbsp;Sandeep Kumar,&nbsp;Arvinder Kaur,&nbsp;Rajesh Kumar Goel","doi":"10.1007/s40203-023-00169-x","DOIUrl":"https://doi.org/10.1007/s40203-023-00169-x","url":null,"abstract":"<p><strong>Background: </strong>Network pharmacology approach has been observed a powerful tool to predict underlying complex pharmacological mechanism of herbs. <i>Asparagus racemosus</i> has been reported to show ameliorative effects in treating epilepsy and comorbid memory dysfunction but mechanism of this amelioration is elusive. Hence a network pharmacology approach was employed to investigate the plausible mechanism of <i>A</i>. <i>recemosus</i>.</p><p><strong>Methodology: </strong>: Bioactive compounds of <i>A. racemosus</i> were extracted based on the TCMSP, PCIDB, and BATMAN-TCM database. The potential targets of bioactive compounds were collected using target fishing. Epilepsy and comorbid dementia genes were collected from DISGENET. A PPI network among these targets was constructed using the intersecting key targets between herb targets and disease targets. Besides, DAVID bioinformatics resource was utilized for the pathway enrichment analysis on GO and KEGG. Ultimately, phytochemical compound-target genes-Pathways network has been assembled utilizing Cytoscape to decipher the mechanism of the herb.</p><p><strong>Results: </strong>The network analysis revealed that 5 targets (CASP3, TNF, VEGFA, PTGS2 and CNR1) might be the key therapeutic targets of asparagus on Epilepsy comorbid Alzheimer's disease. Based on high connectivity, four hub compounds with the highest connectivity were noted and it includes Shatavarin V, Sarsasapogenin, Shatavarin IX, and Shatavarin VI. A total of 19 KEGG terms were enriched as the potential pathways of <i>A. racemosus</i> in Epilepsy comorbid Alzheimer's disease.</p><p><strong>Conclusion: </strong>This study envisaged the pharmacological and molecular mechanism of <i>A. racemosus</i> against epilepsy comorbid Alzheimer's disease and put forward a strategy to uncover the mechanisms of Traditional Indian Medicine based on network pharmacology.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-023-00169-x.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of novel anti-quorum sensing peptides targeting LuxO to combat <i>Vibrio cholerae</i> pathogenesis.","authors":"Janaranjani Murugesan,&nbsp;Shoufia Jabeen Mubarak,&nbsp;Hemamalini Vedagiri","doi":"10.1007/s40203-023-00172-2","DOIUrl":"https://doi.org/10.1007/s40203-023-00172-2","url":null,"abstract":"<p><p><i>Vibrio cholerae</i>, the Gram-negative bacterium abruptly colonizes the human intestine causing diarrhea, employing quorum sensing (QS) system as the major survival technique for mediating biofilm formation, virulence, competence, etc. Two distinct QS systems coordinated by the auto-inducer molecules, cholera-specific CqsA/S system and universal LuxS/PQ system, operate in parallel converging into a common phosphorelay pathway involving LuxU and LuxO. The master regulatory proteins of the QS system, AphA and HapR regulate the biofilm formation based on cell density, whose expression is controlled by the global response regulator LuxO. At low cell density, activated LuxO indirectly represses HapR, favoring the virulence cascade expression. Rather at high cell densities, LuxO represses AphA expression subsequently blocking the expression of virulence factors. Hence, targeting LuxO would be a promising strategy to downregulate the virulence pathway and modulate the QS system. With this insight, the present study has been designed to intrude the interaction between LuxU and LuxO through <i>in silico</i> design of novel peptides and validation of these peptides through molecular simulations. QS peptides were designed using QSPred server by altering the template sequence representing the LuxU-LuxO interaction, among which PEP8 exhibited better interaction and stability with the target protein LuxO. These <i>in silico</i> designed novel peptides would serve as potential target-specific molecules that would inhibit the LuxU-LuxO interaction and modulate the QS system to restrict <i>Vibrio cholerae</i> pathogenesis. However, further in vitro validations would substantiate the efficacy of these novel QS peptides.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-023-00172-2.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug repurposing by in silico prediction of cyclizine derivatives as antihyperlipemic agents.","authors":"M S Afanamol,&nbsp;A Deepika Dinesh,&nbsp;K Shifa Ali,&nbsp;Ajeesh Vengamthodi,&nbsp;Arun Rasheed","doi":"10.1007/s40203-023-00164-2","DOIUrl":"https://doi.org/10.1007/s40203-023-00164-2","url":null,"abstract":"<p><p>Cardiovascular diseases are the primary factor for increased mortality rates around the world. Atherosclerosis brought on by high serum cholesterol can result in coronary heart disease (CHD). The risk of CHD is markedly reduced by lowering serum cholesterol levels. Scientists across the world are inventing new treatment regimens for lowering blood lipid levels. In this work, we repurposed the already established drugs, i.e., cyclizine derivatives as antihyperlipidemic agents. The repurposing was done based on the similarity of the selected cyclizine derivatives with the already established antihyperlipidemic drug, fenofibrate. Computational studies were performed and the 16 cyclizine derivatives docked against PPAR. alpha scored higher than fenofibrate. Lifarizine and medibazine outperform fenofibrate inmmgbsa. Fenofibrate, etodroxizine, meclizine, and cinnarizine had similar mmgbsa scores. The ADME properties of these compounds were performed and from that etodroxizine and levocetirizine were found to have better properties. The computational studies were performed using the Schrodinger software, maestro 12.8. The \"Protein Preparation Wizard\" module in the Maestro panel was used to create the protein structure and OPLS4 force field was used for energy minimization. The maestro builder panel's \"Ligprep\", \"Receptor Grid Generation\" and \"Ligand Docking\" modules were then used to prepare ligands, receptor grids and to perform docking respectively. MMGBSA was performed on the \"prime MMGBSA\" segment. Using the \"Qikprop\" setting in the maestro panel, a number of ADMET properties were predicted, and the program was run in default mode using vsgb as the solvation model.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71416291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insilico design of an allosteric modulator targeting the protein-protein interaction site of 3 Phosphoinositide dependent Kinase-1: design, synthesis and biological activity.","authors":"Vennila Kailasam Natesan, Selvakumar Balaraman, Elango KuppannaGounder Pitchaimuthu","doi":"10.1007/s40203-023-00160-6","DOIUrl":"10.1007/s40203-023-00160-6","url":null,"abstract":"<p><p>The signalling pathways in human cells mostly rely on protein-protein interactions (PPI) for their function. Such a PPI site in 3 Phosphoinositide dependent Kinase-1 (PDK1) is targeted to design the small molecule modulators. Based on the hotspot residues in its PPI site, a pharmacophore with seven different features was developed and screened against 2.9 million lead like compounds in Zinc database. A phthalazine derivative was identified as a potent allosteric inhibitor through virtual screening, molecular docking and 100 ns dynamics simulations. The modified hit possessed hydrogen bonds with Lys115, Arg131, Thr148, Glu150 as well as pi-pi stacking interactions with Phe157 which are the key residues in the PIF pocket of PDK1. Comparison between the free energy profiles by metadynamics simulation with the presence and absence of the modified ligand (MH) in the binding pocket indicates that the binding of MH enhances the hinge motion making PDK1 to adopt open conformation also and stabilizes the fluctuation of the end-to-end distance in αB helix of PDK1. The modified hit compound was synthesized, characterized and found to be cytotoxic to cancerous cells that are rich in PDK1 expression. These results propose that MH can serve as a new scaffold template for the design of novel drugs targeting PDK1 as well as promising allosteric regulator of PDK1 targeting its protein-protein interface.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-023-00160-6.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41165942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-vitro antibacterial, antioxidant and anti-inflammatory and In-silico ADMET, molecular docking study on <i>Hardwickia binata</i> phytocompunds with potential inhibitor of skin cancer protein.","authors":"Peraman Manimegalai, Kuppusamy Selvam, Palanisamy Prakash, Dharmalingam Kirubakaran, Muthugounder Subaramanian Shivakumar, Sengottayan SenthilNathan","doi":"10.1007/s40203-023-00163-3","DOIUrl":"10.1007/s40203-023-00163-3","url":null,"abstract":"<p><p>The new sources of antimicrobial and antioxidant agents for methanol extracts of <i>Hardwickia binata</i> Roxb were evaluated systematically. The present investigation is antibacterial, antioxidant, ADMET and molecular docking studies. Our results show the good polyphenol content (total phenol, total flavonoid) and antioxidant capacity of methanol extracts. The free radical scavenging activities of the methanol extracts also were highest, with the antioxidant activity becoming significantly greater. Furthermore, in-vitro antibacterial experiments against phytopathogens, <i>Enterococcus faecalis</i> have a high zone of inhibition (14 ± 0.54) compared with other pathogens. The functional groups of methanol extract were identified using FTIR. The active molecules from GCMS involved in ADMET and docking study for skin cancer proteins (1P7K and 5OTE) among the phytocompounds, Hexadecanoic acid, methyl ester (- 6.2; - 6.6 kcal/mol) and 5-Phenyl-2,4-pyrimidinediamine, 2TMS derivative (- 7.50; - 8.11 kcal/mol) is the best compound for the human skin cancer possessed higher binding energy. Our results indicate that the plants can provide sources of natural compounds used for moderate good anticancer drug.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41180024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network analysis and molecular docking studies of quercetin as a potential treatment for prostate cancer.","authors":"Frank Kalungi, Anthony Nsubuga, Godwin Anywar","doi":"10.1007/s40203-023-00162-4","DOIUrl":"10.1007/s40203-023-00162-4","url":null,"abstract":"<p><p>Globally, the prevalence of prostate cancer is only the second to lung cancer. In Africa however, the commonest cancer among men is cancer of the prostate. The use of natural compounds from plants such as quercetin is being explored as a potential cure. Quercetin is a plant-based flavonoid that has anti-inflammatory, antioxidant and anticancer properties. Although quercetin has been extensively studied, its chemo preventive mode of action is not well-understood. The molecular targets and potential mechanisms underlying the action of quercetin against prostate cancer were identified and validated using network pharmacology and molecular docking methods. The biological targets of quercetin and targets associated with prostate cancer were obtained through database mining. Overlapping targets associated with quercetin and prostate cancer were identified and used to construct a compound-disease target (C-D) network and the targets were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction analysis (PPI). A disease target- pathway network was constructed and then merged with C-D network to form a compound-disease_target-pathway (C-D-P) network. Hub targets were obtained from the C-D-P and PPI networks. The binding affinities between quercetin and the retrieved hub targets were identified. Pathway enrichment analysis showed that prostate cancer associated quercetin targets were mainly linked with pathways such as the cancer signaling pathways (HIF-1 and ErbB) and hepatitis B. Basing on the PPI and C-D-P network analysis STAT3, TP53, MAPK1, MAPK3 and KRAS were identified as the main targets and were subjected to molecular docking. The results showed quercetin's ability to stably bind to the key targets. In conclusion, this study showed the potential molecular targets and mode of action of quercetin in prostate cancer treatment. This can potentially inform the future use of quercetin in the treatment of prostate cancer.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41172177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}