scholarly journals Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity

2022 ◽  
Vol 44 (1) ◽  
pp. 383-408
Author(s):  
Renata Priscila Barros de Menezes ◽  
Jéssika de Oliveira Viana ◽  
Eugene Muratov ◽  
Luciana Scotti ◽  
Marcus Tullius Scotti

Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products.

Author(s):  
Lihong Li ◽  
Man Yang ◽  
Chenyao Li ◽  
Hongyu Xue ◽  
Meiyun Shi ◽  
...  

Background: HSP90 has been considered as an important anticancer target for several decades, but traditional HSP90 N-terminal inhibitors often suffered from organ toxicity and/or drug resistance. Methods: The development of HSP90 C-terminal inhibitors represents a reliable alternative strategy. In the view of rare examples of structure based identification of HSP90 C-terminal inhibitors, we reported a virtual screening based strategy for the discovery of HSP90 C-terminal inhibitors as anticancer agents from natural products. Results & Discussion: 13 chemical ingredients from licorice were identified as possible HSP90 inhibitors and 3 of them have been reported as anticancer agents. The binding modes of them towards HSP90 C-terminus were predicted by molecular docking and refined by molecular dynamics stimulation. Conclusion: Further network pharmacological analysis predicted overall possible targets involved in the pathways in cancer and revealed that 8 molecules possibly interact with HSP90.


2020 ◽  
Vol 20 (3) ◽  
pp. 223-235
Author(s):  
Pooja Shah ◽  
Vishal Chavda ◽  
Snehal Patel ◽  
Shraddha Bhadada ◽  
Ghulam Md. Ashraf

Background: Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications. Objective: The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes. Material and Methods: In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity. Results: In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate. Conclusion: In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.


2020 ◽  
Vol 18 ◽  
Author(s):  
Debadash Panigrahi ◽  
Ganesh Prasad Mishra

Objective:: Recent pandemic caused by SARS-CoV-2 described in Wuhan China in December-2019 spread widely almost all the countries of the world. Corona virus (COVID-19) is causing the unexpected death of many peoples and severe economic loss in several countries. Virtual screening based on molecular docking, drug-likeness prediction, and in silico ADMET study has become an effective tool for the identification of small molecules as novel antiviral drugs to treat diseases. Methods:: In the current study, virtual screening was performed through molecular docking for identifying potent inhibitors against Mpro enzyme from the ZINC library for the possible treatment of COVID-19 pandemic. Interestingly, some compounds are identified as possible anti-covid-19 agents for future research. 350 compounds were screened based on their similarity score with reference compound X77 from ZINC data bank and were subjected to docking with crystal structure available of Mpro enzyme. These compounds were then filtered by their in silico ADME-Tox and drug-likeness prediction values. Result:: Out of these 350 screened compounds, 10 compounds were selected based on their docking score and best docked pose in comparison to the reference compound X77. In silico ADME-Tox and drug likeliness predictions of the top compounds were performed and found to be excellent results. All the 10 screened compounds showed significant binding pose with the target enzyme main protease (Mpro) enzyme and satisfactory pharmacokinetic and toxicological properties. Conclusion:: Based on results we can suggest that the identified compounds may be considered for therapeutic development against the COVID-19 virus and can be further evaluated for in vitro activity, preclinical, clinical studies and formulated in a suitable dosage form to maximize their bioavailability.


Author(s):  
Suraj N. Mali ◽  
Anima Pandey

Malarial parasites have been reported for moderate-high resistance towards classical antimalarial agents and henceforth development of newer novel chemical entities targeting multiple targets rather than targeting single target will be a highly promising strategy in antimalarial drug discovery. Herein, we carried out molecular modeling studies on 2,4-disubstituted imidazopyridines as anti-hemozoin formation inhibitors by using Schrödinger’s molecular modeling package (2020_4). We have developed statistically robust atom-based 3D-QSAR model (training set, [Formula: see text]; test set, [Formula: see text]; [Formula: see text] [Formula: see text]; root-mean-square error, [Formula: see text]; standard deviation, [Formula: see text]). Our molecular docking, in-silico ADMET analysis showed that dataset molecule 37, has highly promising results. Our ligand-based virtual screening resulted in top five ZINC hits, among them ZINC73737443 hit was observed with lesser energy gap, i.e. 7.85[Formula: see text]eV, higher softness value (0.127[Formula: see text]eV), and comparatively good docking score of [Formula: see text]10.2[Formula: see text]kcal/mol. Our in-silico analysis for a proposed hit, ZINC73737443 showed that this molecule has good ADMET, in-silico nonames toxic as well as noncarcinogenic profile. We believe that further experimental as well as the in-vitro investigation will throw more lights on the identification of ZINC73737443 as a potential antimalarial agent.


2017 ◽  
Author(s):  
Ευτυχία Κρίτση

Στην παρούσα διατριβή πραγματοποιήθηκε εκτενής μελέτη για την αναζήτηση πρόδρομων βιοδραστικών ενώσεων (hits) από χημικές βιβλιοθήκες για τρείς βιολογικούς στόχους, μέσω της εφαρμογής εμπορικά διαθέσιμων in silico τεχνικών και μεθοδολογιών.Οι στόχοι που επιλέχθηκαν ανήκουν σε διαφορετικές κατηγορίες πρωτεϊνών με μεγάλο φαρμακευτικό ενδιαφέρον, που όμως παρουσιάζουν διαφορετικό επίπεδο ωριμότητας όσον αφορά την εφαρμογή υπολογιστικών εργαλείωνγια την ανακάλυψη νέων φαρμακευτικών ενώσεων. Συγκεριμένα, οι στόχοι που μελετήθηκαν είναι οι ακόλουθοι:•το ένζυμο της 14-α διμεθυλάσης της λανοστερόλης (CYP51) για την αναζήτηση νέων πρόδρομων βιοδραστικών ενώσεων με αντιμικροβιακές ιδιότητες,•το ένζυμο της HIV τύπου 1 πρωτεάσης (HIV-1 PR) για την αναζήτηση νέων πρόδρομων βιοδραστικών ενώσεων με αντι-HIV δράση,•ο διαμεμβρανικός υποδοχέας της Αγγειοτασίνης ΙΙ (ΑΤ1) για την αναζήτηση νέων πρόδρομων βιοδραστικών με αντιυπερτασική δράσηΟι κυριότερες τεχνικές που χρησιμοποιήθηκαν για την αναζήτηση πρόδρομων βιοδραστικών ενώσεων περιλαμβάνουν την Εικονική Σάρωση (Virtual Screening) με χρήση Φαρμακοφόρων Μοντέλων (Pharmacophore modeling), τη Μοριακή Πρόσδεση (Molecular Docking), την πρόβλεψη μοριακών ιδιοτήτων καθώς και Προσομοιώσεις Μοριακής Δυναμικής (Molecular Dynamics Simulations). Η στρατηγική που ακολουθήθηκε διαφέρει σημαντικά ανά στόχο όσον αφορά τη μεθοδολογική προσέγγιση και την επιλογή των υπολογιστικών εργαλείων-αλγορίθμων, δίνοντας έμφαση στη συμπληρωματικότητα των αποτελεσμάτων τους. Για την ανάδειξη των πρόδρομων βιοδραστικών ενώσεων, πραγματοποιήθηκαν in vitro βιολογικές δοκιμές των ενώσεων που προτάθηκαν μέσω των υπολογιστικών τεχνικών. Οι ενώσεις που επιλέχθηκαν παρουσίασαν ανασταλτική δράση (ή συγγένεια πρόσδεσης) σε ικανοποιητικό εύρος τιμών 102 nM–μΜ για να χαρακτηριστούν πρόδρομες βιοδραστικές. Μείζονος σημασίας είναι και το γεγονός ότι οι δομικοί σκελετοί των προτεινόμενων ενώσεων για κάθε στόχο, είναι διαφορετικοί τόσο μεταξύ τους όσο και συγκρινόμενοι με τα υφιστάμενα φαρμακευτικά μόρια. Ως εκ τούτου, μπορούν να αποτελέσουν κατάλληλα "υποστρώματα" για το επόμενο στάδιο που αφορά τη βελτιστοποίησή τους προς ενώσεις-οδηγούς (hit to lead optimization) και δυνητικά προς νέα φαρμακευτικά προϊόντα.


Author(s):  
A. Amala Lourthuraj ◽  
M. Masilamani Selvam ◽  
Bharathi Ravikrishnan ◽  
M. Vinoth ◽  
Waheeta Hopper

Objective: The present research was aimed to understand the molecular docking efficiency of a plant-derived compound cleistanthin-A and a common ingredient in tobacco consumption nicotine with nicotinic acetylcholine receptor (nAChR).Methods: The 3-D structure of nAChR was retrieved from the protein data bank (ID 5AFH). Ligand was obtained from the PUBCHEM. The in silico protocol comprised of three steps: high-throughput virtual screening (HTVS), standard preci­sion (SP) and extra precision (XP). The screened molecules were ranked accordingly using glide score. Schrödinger tool was used to perform the docking analysis.Results: The binding efficiency of the nicotine and cleistanthin-A was found to be docked at the cys-cys loop of the receptor. Based upon the glide score and glide energy it can be reported that, nicotine binding can be inhibited by the binding of cleistanthin-A to the nAChR.Conclusion: The docking efficiency of cleistanthin-A was good compared to nicotine towards nAChR. Hence, cleistanthin–A was derived as a better choice as an alternative for nicotine in smoke therapy.


2020 ◽  
Vol 15 (9) ◽  
pp. 1934578X2095326
Author(s):  
Jai-Sing Yang ◽  
Jo-Hua Chiang ◽  
Shih‑Chang Tsai ◽  
Yuan-Man Hsu ◽  
Da-Tian Bau ◽  
...  

The coronavirus disease 2019 (COVID‐19) outbreak caused by the 2019 novel coronavirus (2019-nCOV) is becoming increasingly serious. In March 2019, the Food and Drug Administration (FDA) designated remdesivir for compassionate use to treat COVID-19. Thus, the development of novel antiviral agents, antibodies, and vaccines against COVID-19 is an urgent research subject. Many laboratories and research organizations are actively investing in the development of new compounds for COVID-19. Through in silico high-throughput virtual screening, we have recently identified compounds from the compound library of Natural Products Research Laboratories (NPRL) that can bind to COVID-19 3Lpro polyprotein and block COVID-19 3Lpro activity through in silico high-throughput virtual screening. Curcuminoid derivatives (including NPRL334, NPRL339, NPRL342, NPRL346, NPRL407, NPRL415, NPRL420, NPRL472, and NPRL473) display strong binding affinity to COVID-19 3Lpro polyprotein. The binding site of curcuminoid derivatives to COVID-19 3Lpro polyprotein is the same as that of the FDA-approved human immunodeficiency virus protease inhibitor (lopinavir) to COVID-19 3Lpro polyprotein. The binding affinity of curcuminoid derivatives to COVID-19 3Lpro is stronger than that of lopinavir and curcumin. Among curcuminoid derivatives, NPRL-334 revealed the strongest binding affinity to COVID-19 3Lpro polyprotein and is speculated to have an anti-COVID-19 effect. In vitro and in vivo ongoing experiments are currently underway to confirm the present findings. This study sheds light on the drug design for COVID-19 3Lpro polyprotein. Basing on lead compound development, we provide new insights on inhibiting COVID-19 attachment to cells, reducing COVID-19 infection rate and drug side effects, and increasing therapeutic success rate.


ALCHEMY ◽  
2016 ◽  
Vol 5 (2) ◽  
pp. 45
Author(s):  
Sandra Hermanto

Penapisan peptida bioaktif dari hidrolisat kasein susu kambing Etawa yang berpotensi sebagai obat antihipertensi berdasarkan kajian <em>in silico </em>telah dilakukan. Protein yang digunakan adalah α-S1-kasein prekursor [<em>Capra hircus</em>] NCBI <em>Reference Sequence</em>: NP_001272624.1, α-S2-kasein prekursor [<em>C. hircus</em>] NCBI <em>Reference Sequence</em>: NP_001272514.1, β-kasein [<em>C. hircus</em>] NCBI <em>Reference Sequence</em>: AAA30906.1 dan κ-kasein prekursor [<em>C. hircus</em>] NCBI <em>Reference Sequence</em>: NP_001272516.1. Perancangan struktur peptida bioaktif dilakukan melalui simulasi hidrolisis enzimatik dengan menggunakan 3 jenis enzim proteolitik (tripsin, kimotripsin dan pepsin) dan dilanjutkan dengan preparasi struktur 3D ligan hasil pemotongan secara <em>in silico</em>. <em>Virtual screening</em> terhadap fragmen peptida dilakukan melalui penentuan nilai <em>drug likeness</em> dan <em>protease inhibitor.</em> Dari 104 fragmen peptida diperoleh 10 kandidat peptida bioaktif yang dilakukan simulasi <em>molecular docking</em> dengan mengeksplorasi daya inhibisi fragmen melalui perhitungan nilai (∆<em>G<sub>binding</sub></em>) dan interaksi antara kandidat peptida bioaktif dengan residu asam amino pada sisi aktif enzim ACE (<em>Angiotensin Converting Enzyme)</em>. Sebagai kontrol positif digunakan lisinopril yang merupakan inhibitor ACE komersil. Hasil penelitian menunjukkan dari 10 kandidat peptida bioaktif terdapat 6 peptida yang diduga bersifat antihipertensi dengan nilai ∆<em>G<sub>binding</sub></em><em></em><sub> </sub>yang lebih rendah dari kontrol positif (lisinopril). Keenam peptida tersebut diharapkan dapat berfungsi sebagai obat alternatif antihipertensi.


2018 ◽  
Author(s):  
Mukta Sharma ◽  
Anupama Mittal ◽  
Aarti Singh ◽  
Ashwin K. Jainarayanan ◽  
Sarvesh Kumar Paliwal

ABSTRACTIn view of “excitotoxic” effects of glutamate, wherein excessive excitatory input causes increase in intracellular Ca2+ and ultimately cell death, NMDA receptor has emerged as an important target for treatment and prevention of several neurological disorders, like Alzheimer disease. Prompted by the successful application of in-silico pharmacophore-based virtual screening in lead identification, we have made an effort to implement in-silico protocols to identify novel NMDA receptor antagonist. A series of novel benzo[b]quinolizinium cations as NMDA receptor antagonists have been used as a starting point to develop prognostic pharmacophore models. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, one hydrogen bond acceptor, one hydrophobic and two ring aromatic, showed a correlation (r) of 0.89, root mean square of 0.259, and the cost difference of 43.01 bits between null and fixed cost. The model was thoroughly validated and subjected to a chemical database search, which lead to the identification of 400 hits from NCI and Maybridge databases which were checked for Lipinski’s violation and predictive potency.This reduced the list to 10 compounds, out of which, two most potent compounds were subjected to molecular docking using Libdock software and interestingly, all the docked conformations showed hydrogen bond interactions with important amino acids Tyr214, His88, Thr174, Val169 and Arg121. In summary, through our validated pharmacophore-based virtual screening protocol, we have identified two potent, structurally diverse, druggable and novel NMDA receptor antagonist which might be of great help to address the unmet medical need of Alzheimer disease.


Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 59
Author(s):  
Muthu Kumar Thirunavukkarasu ◽  
Utid Suriya ◽  
Thanyada Rungrotmongkol ◽  
Ramanathan Karuppasamy

The RAS–RAF–MEK–ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.


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