In silico pharmacology最新文献

{"title":"Exploring the therapeutic potential of prolinamides as multi-targeted agents for Alzheimer's disease treatment: molecular docking and molecular dynamic simulation studies.","authors":"Samuel O Olalekan, Vincent A Obakachi, Abosede A Badeji, Oyesolape B Akinsipo Oyelaja, Oluwole Familoni, Olayinka T Asekun, Segun D Oladipo, Adejoke D Osinubi","doi":"10.1007/s40203-024-00250-z","DOIUrl":"10.1007/s40203-024-00250-z","url":null,"abstract":"<p><p>Alzheimer's disease (AD) presents a significant global health challenge, with its prevalence expected to rise sharply in the coming years. Despite extensive research, effective treatments addressing the multifaceted pathophysiology of AD remain elusive. This study investigates the therapeutic potential of twenty-seven prolinamides (P1 - P27), with the focus on their interactions with key proteins implicated in AD pathogenesis. Four of the compounds, namely; 10-((4-nitrophenyl)prolyl)-10 H-phenothiazine (P14), 2-((4-nitrophenyl)prolyl)isoindoline (P19), 1-(4-formylphenyl)-<i>N</i>-(p-tolyl)pyrrolidine-2-carboxamide (P22), and <i>N</i>,1-bis(4-nitrophenyl)pyrrolidine-2-carboxamide (P27) showed promising potential as Alzheimer's drug. In-silico approaches including molecular docking, molecular dynamic (MD) simulation, post md study, physicochemical and drug-likeness parameters were employed to ascertain the potential of these compounds as inhibitors of certain proteins implicated in the pathophysiology of Alzheimer's disease. Molecular docking and dynamics simulations demonstrated that P14, P19, P22 and P27 exhibited promising binding affinities towards crucial AD-associated proteins, including Beta-Secretase 1 (BACE1), Butyrylcholinesterase (BuChE), and Tau-tubulin kinase 2 (TTBK2). Structural stability analyses revealed that prolinamides, particularly P22 and P27 for BACE1 and P14 and P19 for BuChE, exhibited greater stability than their reference ligands, indicated by lower RMSD, RoG, and RMSF values. For BuChE, Rivastigmine had a docking score of -7.0 kcal/mol, a binding free energy (ΔG_bind) of -22.19 ± 2.44 kcal/mol, RMSD of 1.361 ± 0.162 Å, RMSF of 9.357 ± 3.212 Å, and RoG of 22.919 ± 0.064 Å, whereas P19 exhibited a superior docking score of -10.3 kcal/mol, a significantly better ΔG_bind of -33.74 ± 2.84 kcal/mol, RMSD of 1.347 ± 0.132 Å, RMSF of 8.164 ± 2.748 Å, and RoG of 22.868 ± 0.070 Å. Physicochemical and pharmacokinetic assessments affirmed the drug-likeness and bioavailability of P19 notably capable of penetrating the blood-brain barrier. Compounds P19 and P22, emerged as multi-targeted ligands, offering the potential for simultaneous modulation of multiple AD-related pathways. These findings highlight the possibilities of these compounds to be explored as novel therapeutic agents for AD. They also highlight the need for further experimental validation to confirm their efficacy and safety profiles, advancing them toward clinical application in AD management.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00250-z.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121435","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":"Pharmacophore mapping, 3D QSAR, molecular docking, and ADME prediction studies of novel Benzothiazinone derivatives.","authors":"Jahaan Shaikh, Salman Patel, Afzal Nagani, Moksh Shah, Siddik Ugharatdar, Ashish Patel, Drashti Shah, Dharti Patel","doi":"10.1007/s40203-024-00255-8","DOIUrl":"10.1007/s40203-024-00255-8","url":null,"abstract":"<p><p>In the quest to combat tuberculosis, DprE1, a challenging target for novel anti-tubercular agents due to its small size and membrane location, has been a focus of research. DprE1 catalyzes the transformation of DPR into Ketoribose DPX, with Benzothiazinone emerging as a potent pharmacophore for inhibiting DprE1. Clinical trial drugs such as BTZ043, BTZ038, PBTZ169, and TMC-207 have shown promising results as DprE1 inhibitors. This study employed pharmacophore mapping of Pyrazolopyridine, Dinitrobenzamide, and Benzothiazinone derivatives to identify crucial features for eliciting a biological response. Benzothiazinone (Ligand code: 73) emerged as a reference ligand with a fitness score of 3.000. ROC analysis validated the pharmacophore with an excellent score of 0.71. To build a 3D QSAR model, a series of Benzothiazinone congeneric derivatives were explored. The model exhibited strong performance, with a standard deviation of 0.1531, a correlation coefficient for the training set (R²) value of 0.9754, and a correlation coefficient for test set Q² value of 0.7632, indicating robust predictive capabilities. Contour maps guided the design of novel benzothiazinone derivatives, emphasizing steric, electrostatic, hydrophobic, H-bond acceptor, and H-bond donor groups for structure-activity relationships. Docking studies against PDB ID: 4NCR demonstrated favorable scores, with interactions aligning well with the in-built ligand 26 J. Docking validation via RMSD values supported the reliability of the docking results. This comprehensive approach aids in the design of novel benzothiazinone derivatives with potential anti-tubercular properties, contributing to the development of novel anti-tubercular agents which can be pivotal in the eradication of tuberculosis.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116472","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":"Antibacterial activity of natural flavones against bovine mastitis pathogens: in vitro, SAR analysis, and computational study.","authors":"Ahlam Haj Hasan, Gagan Preet, Rishi Vachaspathy Astakala, Hanan Al-Adilah, Emmanuel Tope Oluwabusola, Rainer Ebel, Marcel Jaspars","doi":"10.1007/s40203-024-00253-w","DOIUrl":"10.1007/s40203-024-00253-w","url":null,"abstract":"<p><p>Bovine mastitis is a worldwide disease affecting dairy cattle and causes major economic losses in the dairy industry. Recently, the emergence of microbial resistance to the current antibiotics complicates the treatment protocol which necessitates antibiotic stewardship and further research to find new active compounds. Recently, phytobiotics have gained interest in being used as an alternative to antibiotics in the poultry industry as an antibiotic stewardship intervention. This study evaluated the in vitro antibacterial activity of 16 flavonoids against bovine mastitis pathogens. Two flavones: 2-(4-methoxyphenyl)chromen-4-one (<b>1</b>) and 2-(3-hydroxyphenyl)chromen-4-one (<b>4</b>) showed inhibition of the growth of <i>Klebsiella oxytoca</i> with MIC values range (25-50 µg mL^- 1) followed by a structure-activity relationship (SAR) study indicating that the presence of a hydroxyl group at C-3` or methoxy at C-4` increases the activity against <i>Klebsiella oxytoca</i> while the presence of hydroxyl group at C-7 decreases the activity. Furthermore, a structure-based drug development approach was applied using several in silico tools to understand the interactions of active flavones at the active site of the DNA gyrase protein. Compound (<b>4</b>) showed a higher docking score than quercetin (standard) which is known to have antibacterial activity by inhibiting the DNA gyrase. In addition, the structure-based pharmacophores of compound (<b>4</b>) and quercetin showed similar pharmacophoric features and interactions with DNA gyrase. Based on our findings, compounds (<b>1</b>) and (<b>4</b>) are promising for further study as potential anti-microbial phytochemicals that can have a role in controlling bovine mastitis as well as to investigate their mechanism of action further.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00253-w.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057662","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":"Optimization of wet granulation process for manufacturing Rivaroxban generic immediate-release tablets using PBPK modeling and simulations.","authors":"Jailani Shiekmydeen, Tanisha, Sonam Sharma, Kishor Chakraborty, Dhanapal Chidambaram Kannaiyan, Noohu Abdulla Khan, Rajkumar Malayandi","doi":"10.1007/s40203-024-00249-6","DOIUrl":"10.1007/s40203-024-00249-6","url":null,"abstract":"<p><p>Granulation is the critical process for the pharmaceutical development of poorly water-soluble drug products. Poorly formulated products have challenges in dissolution and bioequivalence studies. Rivaroxaban (RXB) is a poorly soluble drug and has 66% fasting bioavailability at a high strength of 20 mg. Establishing the bioequivalence between test and reference products for high strength requires comparative dissolution profiles and bioequivalence. Improper granulation products and the rest of the batches failed in virtual bioequivalence. The present study provided insight into the optimization of the wet granulation process for manufacturing RXB generic immediate-release tablets using PBPK modeling and simulations. Furthermore, PBPK models are not only useful for formulation optimization but also for process optimization during pharmaceutical product development.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00249-6.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11341787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057664","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-silico binding affinity of a phage display library screened novel peptide against various FABPs.","authors":"Harshita Shand, Soumendu Patra, Bavya Chandrasekhar, Sharvari Kulkarni, Thirumurthy Madhavan, Suvankar Ghorai","doi":"10.1007/s40203-024-00251-y","DOIUrl":"10.1007/s40203-024-00251-y","url":null,"abstract":"<p><p>In accordance to the American Heart Association (AHA), cardiovascular diseases (CVDs) are the leading cause of death around the globe, causing more than 19.1 million deaths in 2020. Heart-type fatty acid binding protein (H-FABP) is required for the metabolism of fatty acids (FA) inside cardiomyocytes is reported as a biomarker for myocardial damage. As early as one hour after an Acute myocardial infarction (AMI), H-FABP can be used to detect myocardial ischemia. Thus, H-FABP based detection can reduce the burden on the emergency department. A peptide-based detection system can provide point-of-care diagnostics for CVDs. There is a lot of research being done on peptide-based detection, and it has a lot of potential to help with unmet medical diagnostic needs. A twelve (12) amino acid peptide has been discovered using Phage Display Library Screening. The affinity of peptide with H-FABP and other FABPs has been done using molecular docking and ADMET profile has been done. Molecular docking of small peptides against the target protein can play a crucial role in recognizing peptide binding sites and poses. The docking study was done using the HDOCK server and the visualization of the docked complex was done using Pymol and UCSF chimera. The molecular simulation study of three protein-peptide complexes were done which also validated the binding affinity of peptide with the proteins. The RMSD, RMSF and radius of gyration are also analyzed. The results indicate that H-FABP shows higher level of binding interaction with the peptide having bond length ranging from 2.3 to 3.4 Å. The screened peptide is suitable for H-FABP binding and can be used for prognosis purposes in the heart ischemic conditions.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057663","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 silico analysis of balsaminol as anti-viral agents targeting SARS-CoV-2 main protease, spike receptor binding domain and papain-like protease receptors.","authors":"Daniel Danladi Gaiya, Aliyu Muhammad, Joy Sim Musa, Richard Auta, Anthony John Dadah, Rachael Oluwafunmilayo Bello, Madinat Hassan, Samuel Sunday Eke, Rebecca Imoo Odihi, Musa Sankey","doi":"10.1007/s40203-024-00241-0","DOIUrl":"10.1007/s40203-024-00241-0","url":null,"abstract":"<p><p>Plant-derived phytochemicals from medicinal plants are becoming increasingly attractive natural sources of antimicrobial and antiviral agents due to their therapeutic value, mechanism of action, level of toxicity and bioavailability. The continued emergence of more immune-evasive strains and the rate of resistance to current antiviral drugs have created a need to identify new antiviral agents against SARS-CoV-2. This study investigated the antiviral potential of balsaminol, a bioactive compound from <i>Momordica balsamina</i>, and its inhibitory activities against SARS-CoV-2 receptor proteins. In this study, three Food and Drug Administration (FDA) COVID-19 approved drugs namely; nirmatrelvir, ritonavir and remdesivir were used as positive control. Molecular docking was performed to determine the predominant binding mode (most negative Gibbs free energy of binding/ΔG) and inhibitory activity of balsaminol against SARS-CoV-2 receptor proteins. The pharmacokinetics, toxicity, physicochemical and drug-like properties of balsaminol were evaluated to determine its potential as an active oral drug candidate as well as its non-toxicity in humans. The results show that balsaminol E has the highest binding affinity to the SARS CoV-2 papain-like protease (7CMD) with a free binding energy of - 8.7 kcal/mol, followed by balsaminol A interacting with the spike receptor binding domain (6VW1) with - 8.5 kcal/mol and balsaminol C had a binding energy of - 8.1 kcal/mol with the main protease (6LU7) comparable to the standard drugs namely ritonavir, nirmatrelvir and remdesivir. However, the ADMET and drug-like profile of balsaminol F favours it as a better potential drug candidate and inhibitor of the docked SARS-CoV-2 receptor proteins. Further preclinical studies are therefore recommended.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00241-0.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001602","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":"Reporting the anti-neuroinflammatory potential of selected spondias mombin flavonoids through network pharmacology and molecular dynamics simulations.","authors":"John A Olanrewaju, Leviticus O Arietarhire, Oladimeji E Soremekun, Ezekiel A Olugbogi, Precious O Aribisala, Pelumi E Alege, Stephen O Adeleke, Toluwanimi O Afolabi, Abayomi O Sodipo","doi":"10.1007/s40203-024-00243-y","DOIUrl":"10.1007/s40203-024-00243-y","url":null,"abstract":"<p><p>Neuroinflammation plays a pivotal role in the development and progression of neurodegenerative diseases, with a complex interplay between immune responses and brain activity. Understanding this interaction is crucial for identifying therapeutic targets and developing effective treatments. This study aimed to explore the neuroprotective properties of flavonoid compounds from <i>Spondias mombin</i> via the modulation of neuroinflammatory pathway using a comprehensive in-silico approach, including network pharmacology, molecular docking, and dynamic simulations. Active flavonoid ingredients from <i>S. mombin</i> were identified, and their potential protein targets were predicted through Network Pharmacology. Molecular docking was conducted to determine the binding affinities of these compounds against targets obtained from network pharmacology, prioritizing docking scores ≥ - 8.0 kcal/mol. Molecular dynamic simulations (MDS) assessed the stability and interaction profiles of these ligand-protein complexes. The docking study highlighted ≥ - 8.0 kcal/mol for the ligands (catechin and epicatechin) against FYN kinase as a significant target. However, these compounds failed the blood-brain barrier (BBB) permeability test. MDS confirmed the stability of catechin and the reference ligand at the FYN kinase active site, with notable interactions involving hydrogen bonds, hydrophobic contacts, and water bridges. GLU54 emerged as a key residue in the catechin-FYN complex stability due to its prolonged hydrogen bond interaction. The findings underscore the potential of <i>S. mombin</i> flavonoids as therapeutic agents against neuroinflammation, though optimization and nanotechnology-based delivery methods are suggested to enhance drug efficacy and overcome BBB limitations.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001603","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":"Elucidation and active ingredient identification of aqueous extract of <i>Ficus exasperata</i> Vahl leaf against bisphenol A-induced toxicity through in vivo and in silico assessments.","authors":"Olugbenga Eyitayo Adeyemi, Kiri Hashimu Jaryum, Titilayo Omolara Johnson","doi":"10.1007/s40203-024-00248-7","DOIUrl":"10.1007/s40203-024-00248-7","url":null,"abstract":"<p><p>Bisphenol A (BPA), an endocrine-disrupting chemical, poses significant health problems due to its induction of oxidative stress, inflammation, etc. Whereas <i>Ficus exasperata</i> Vahl leaf (FEVL) was reported for its ethnopharmacological properties against several ailments owing to its antioxidant, anti-inflammatory properties, etc. Here, we aim to elucidate and identify the bioactive compounds of aqueous extract of FEVL (AEFEVL) against BPA-induced toxicity using in vivo and in silico assessments. To determine the BPA toxicity mechanism and safe doses of AEFEVL, graded doses of BPA (0-400 μM) and AEFEVL (0-2.0 mg/10 g diets) were separately fed to flies to evaluate survival rates and specific biochemical markers. The mitigating effect of AEFEVL (0.5 and 1.0 mg/10 g diet) against BPA (100 and 200 μM)-induced toxicity in the flies after 7-day exposure was also carried out. Additionally, molecular docking analysis of BPA and BPA-o-quinone (BPAQ) against selected antioxidant targets, and HPLC-MS-revealed AEFEVL compounds against Keap-1 and IKKβ targets, followed by ADMET analysis, was conducted. Emergence rate, climbing ability, acetylcholinesterase, monoamine oxidase-B, and glutathione-<i>S</i>-transferase activities, and levels of total thiols, non-protein thiols, nitric oxide, protein carbonyl, malondialdehyde, and cell viability were evaluated. BPA-induced altered biochemical and behavioral parameters were significantly mitigated by AEFEVL in the flies (p < 0.05). BPAQ followed by BPA exhibited higher inhibitory activity, and epigallocatechin (EGC) showed the highest inhibitory activity among the AEFEVL compounds with desirable ADMET properties. Conclusively, our findings revealed that EGC might be responsible for the mitigative effect displayed by AEFEVL in BPA-induced toxicity in <i>D. melanogaster</i>.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141984214","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":"Recuperative potential of Indian medicinal plant compounds- a tool to encumber henipaviruses: an in -silico study.","authors":"Sukanth Kumar Enmozhi, Infant Xavier, Theepan Raaj, R Sarveswaran, Jeba Blessings, Yugesh Kesavamoorthy, Rahul Vivek, Kavitha Raja, Irudhayasamy Sebastine, Antony Jeffri, Sumathy Arockiasamy, Jerrine Joseph, Ananda Rani","doi":"10.1007/s40203-024-00236-x","DOIUrl":"10.1007/s40203-024-00236-x","url":null,"abstract":"<p><p>Henipaviruses, highly fatal zoonotic viruses with mortality rates up to 100%, pose a significant threat to humans. Despite sporadic cases, including infections from Cedar, Langya, and Nipah Viruses, there are no established drugs or vaccines for treatment. This lack of specific medication led us to explore 57 non-toxic compounds from Indian Medicinal Plants, selected from 232 compounds, aiming to combat these viruses. Through in silico ADMET analyses, Three compounds-andrographolide, pterygospermin and Salidroside-stood out for their exceptional non-toxic properties. These compounds underwent in silico target prediction, molecular docking and dynamics with Cedar, Langya, and Nipah Virus proteins from the Protein Data Bank. Among them, Andrographolide displayed the most promising negative free energy scores and stability in Cedar Virus-Attachment G-Protein binding pockets. Pterygospermin and Salidroside showed efficacy against Langya and Nipah Virus target proteins throughout the simulation. These compounds not only exhibited antiviral properties but also demonstrated immunomodulatory, anti-inflammatory, and hepatoprotective effects by our in-silico studies. Their potential as treatments or preventive measures against henipaviral infections makes them promising candidates for further research and development.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00236-x.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891373","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":"Comparative in silico analysis of CNS-active molecules targeting the blood-brain barrier choline transporter for Alzheimer's disease therapy.","authors":"Sergey Shityakov, Carola Y Förster, Ekaterina Skorb","doi":"10.1007/s40203-024-00245-w","DOIUrl":"10.1007/s40203-024-00245-w","url":null,"abstract":"<p><p>This study investigated the blood‒brain barrier (BBB) permeability of the central nervous system (CNS)-active compounds donepezil (DON), methionine (MET), and memantine (MEM) by employing a comprehensive in silico approach. These compounds are of particular interest for Alzheimer's disease (AD) therapy. Rigid-flexible molecular docking simulations indicated favorable binding affinities of all the compounds with BBB-ChT, with DON exhibiting the highest binding affinity (ΔG_bind = -10.26 kcal/mol), predominantly mediated by significant hydrophobic interactions. In silico kinetic profiling suggested the stability of the DON/BBB-ChT complex, with ligand release prompted by conformational changes. 3D molecular alignment corroborated a minor conformational shift for DON in its minimal binding energy pose. Predictions indicated that active transport mechanisms notably enhance the brain distribution of donepezil compared to that of MET and MEM. Additionally, DON and MEM exhibited low mutagenic probabilities, while MET was identified as highly mutagenic. Overall, these findings highlight the potential of donepezil for superior BBB penetration, primarily through active transport mechanisms, underscoring the need for further validation through in vitro and in vivo studies for effective AD treatment.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-024-00245-w.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891372","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}