Structure‐based virtual screening and computational study towards identification of novel inhibitors of hypoxanthine‐guanine phosphoribosyltransferase of Trypanosoma cruzi

2021 ◽  
Author(s):  
Venkataramani Malathi Vidhya ◽  
Karthe Ponnuraj
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Computational Study ◽  
Hypoxanthine Guanine Phosphoribosyltransferase

scholarly journals Virtual Screening of Marine Natural Compounds by Means of Chemoinformatics and CDFT-Based Computational Peptidology

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 478
Author(s):  
Norma Flores-Holguín ◽  
Juan Frau ◽  
Daniel Glossman-Mitnik
Keyword(s):  
Virtual Screening ◽  
Density Functional ◽  
Computational Study ◽  
Molecular System ◽  
Chemical Reactivity ◽  
Conceptual Density Functional Theory ◽  
Qsar Studies ◽  
Biological Targets ◽  
Global And Local

This work presents the results of a computational study of the chemical reactivity and bioactivity properties of the members of the theopapuamides A-D family of marine peptides by making use of our proposed methodology named Computational Peptidology (CP) that has been successfully considered in previous studies of this kind of molecular system. CP allows for the determination of the global and local descriptors that come from Conceptual Density Functional Theory (CDFT) that can give an idea about the chemical reactivity properties of the marine natural products under study, which are expected to be related to their bioactivity. At the same time, the validity of the procedure based on the adoption of the KID (Koopmans In DFT) technique, as well as the MN12SX/Def2TZVP/H2O model chemistry is successfully verified. Together with several chemoinformatic tools that can be used to improve the process of virtual screening, some additional properties of these marine peptides are identified related to their ability to behave as useful drugs. With the further objective of analyzing their bioactivity, some useful parameters for future QSAR studies, their predicted biological targets, and the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) parameters related to the theopapuamides A-D pharmacokinetics are also reported.

scholarly journals Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

Molecules ◽  
2017 ◽  
Vol 22 (6) ◽  
pp. 1015 ◽  
Author(s):  
Isidro Palos ◽  
Edgar E. Lara-Ramirez ◽  
Julio Cesar Lopez-Cedillo ◽  
Carlos Garcia-Perez ◽  
Muhammad Kashif ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
In Vivo Studies ◽  
Screening In Vitro ◽  
Cruzain Inhibitors

scholarly journals Virtual Screening of Marine Natural Compounds by Means of Chemoinformatics and CDFT-Based Computational Peptidology

2020 ◽  
Author(s):  
Norma Flores-Holguín ◽  
Juan Frau ◽  
Daniel Glossman-Mitnik
Keyword(s):  
Virtual Screening ◽  
Density Functional ◽  
Computational Study ◽  
Chemical Reactivity ◽  
Conceptual Density Functional Theory ◽  
Qsar Studies ◽  
Molecular Systems ◽  
Biological Targets ◽  
Global And Local

This work presents the results of a computational study of the chemical reactivity and bioactivity properties of the members of the Theopapuamides A-D family of marine peptides by making use of our own proposed methodology named Computational Peptidology (CP) that has been successfully considered in previous studies of this kind of molecular systems. CP allowed for the determination of the global and local descriptors that come from Conceptual Density Functional Theory (CDFT) that can give an idea of the chemical reactivity properties of the marine natural products under study which are already known to be related to their bioactivity. At the same time, the validity of the procedure based on the adoption of the KID (Koopmans in DFT) technique as well as the MN12SX/Def2TZVP/H2O model chemistry has been successfully verified. Together with several Chemoinformatic tools that can be used for the improvement of process of Virtual Screening, some additional properties of these marine peptides were identified related to their ability to behave as useful drugs. With the further object of analyzing their bioactivity some parameters of usefulness for future QSAR studies, their predicted biological targets and the the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) parameters related to the Theopapuamides A-D pharmacokinetics are also reported.

scholarly journals Virtual Screening Based on QSAR and Molecular Docking of Possible Inhibitors Targeting Chagas CYP51

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
J. Cotuá ◽  
H. LLinás ◽  
S. Cotes
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Regression Models ◽  
Rational Design ◽  
Linear Regression Models ◽  
Wide Range ◽  
London Dispersion ◽  
Reduced Toxicity ◽  
Therapeutic Alternatives ◽  
London Dispersion Forces

Chagas is a neglected tropical disease caused by the parasite Trypanosoma cruzi with no effective treatment in all its forms. There is a need to find more effective therapeutic alternatives with reduced toxicity. In this contribution, multiple linear regression models were used to identify the molecular descriptors that best describe the inhibitory activity of 52 fenarimol analogues against Trypanosoma cruzi. The topological, physicochemical, thermodynamic, electronic, and charge descriptors were evaluated to cover a wide range of properties that frequently encode biological activity. A model with high predictive value was obtained based on geometrical descriptors and descriptors encoding hydrophobicity and London dispersion forces as necessary for the inhibition of Trypanosoma cruzi-CYP51. Docking methodology was implemented to evaluate molecular interactions in silico. The virtual screening results in this study can be used for rational design of new analogues with improved activity against Chagas disease.

scholarly journals Design of Potential SARS-CoV-2 Inhibitor

2020 ◽  
Vol 5 (9) ◽  
pp. 1043-1048
Author(s):  
F. J. Amaku ◽  
I. E. Otuokere ◽  
K. K. Igwe ◽  
O. V. Ikpeazu
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Drug Interaction ◽  
Virtual Screening ◽  
Computational Study ◽  
Enzymatic Reaction ◽  
Target Protein ◽  
Web Servers ◽  
Zinc Database ◽  
Online Web

This computational study comprises of pharmacophore-base virtual screening of the ZINC database, molecular docking of predicted ligands (pharmacophore agent) against the target protein, SARS-CoV-2 (PDB ID: 5r7y) and the prediction of ADMET descriptors using Swiss ADME and PROTOX-II online web servers.  Meanwhile,  remdesivir, ZINC72392503, ZINC72809903, ZINC06560017, ZINC76101700, ZINC88423098 and ZINC91600695 had a docking scores of -2.0 Kcal/mol, -6.7 Kcal/mol, -6.4 Kcal/mol, -6.0 Kcal/mol, -6.0 Kcal/mol, -6.0 Kcal/mol and-6.0 Kcal/mol respectively.  Meanwhile, ZINC72392503 was selected as the lead molecule and was observed to interact with LUE 27, THR 25, CYS 145, THR 26, SER 46, GLY 143, ASN 142, HIS 163, HIS 41, MET 165, GLU 166, ARG 188, GLN 189, HIS 41, MET 49, SER 46 amino acids.  The ADME descriptor revealed that the lead molecule was soluble, druggable, void of drug-drug interaction that may inhibit essential enzymatic reaction and was noticed to fall into PROTOX-II toxicity class 3.  The lead molecule showed a good affinity for the target protein of SARS-CoV-2, hence, may have a physiological implication that can inhibit a protein responsible for the replication of SARS-CoV-2.

scholarly journals Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors

2019 ◽  
Vol 20 (7) ◽  
pp. 1742 ◽  
Author(s):  
Verónica Herrera-Mayorga ◽  
Edgar Lara-Ramírez ◽  
Karla Chacón-Vargas ◽  
Charmina Aguirre-Alvarado ◽  
Lorena Rodríguez-Páez ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Selection Process ◽  
Chronic Phase ◽  
Inhibitory Effect ◽  
Pharmacological Treatments ◽  
Trypanocidal Activity ◽  
Trypanocidal Drugs ◽  
Cruzain Inhibitors

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 μM) and trypomastigote (IC50 = 166.21 ± 14.5 μM and 185.1 ± 8.5 μM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

Computational study of the mechanism of half-reactions in class 1A dihydroorotate dehydrogenase from Trypanosoma cruzi

2013 ◽  
Vol 15 (43) ◽  
pp. 18863 ◽  
Author(s):  
Natália de Farias Silva ◽  
Jerônimo Lameira ◽  
Cláudio Nahum Alves ◽  
Sergio Martí
Keyword(s):  
Trypanosoma Cruzi ◽  
Computational Study ◽  
Dihydroorotate Dehydrogenase

New Trypanosoma cruzi Trypanothione Reductase Inhibitors Identification using the Virtual Screening in Database of Nucleus Bioassay, Biosynthesis and Ecophysiology (NuBBE)

2019 ◽  
Vol 17 (2) ◽  
pp. 138-149
Author(s):  
Nelcí do Carmo Santos ◽  
Vinícius G. da Paixão ◽  
Samuel S. da Rocha Pita
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Conclusive Evidence ◽  
New Drugs ◽  
Trypanothione Reductase ◽  
Efficacy And Safety ◽  
Reductase Inhibitors ◽  
Preclinical Trials

Background: American trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi (T. cruzi) and affects approximately 10 to 12 million, primarily in Latin America. Since its discovery in 1909, there is no effective treatment for its chronic phase, with benzonidazole being the only anti-trypanosoma drug used in Brazil, despite the absence of conclusive evidence to prove its efficacy and safety. Thus, it is necessary to develop new drugs that are more effective and selective against Trypanosoma cruzi. Methods: The T. cruzi enzyme Trypanothione Reductase (TcTR) is a validated target for the discovery of new antiprotozoal compounds and we employed the Virtual Screening technique on the database of Nucleus of Bioassays, Biosynthesis and Ecophysiology (NuBBE), aiming to search for new chemical moieties against T. cruzi. From these we selected the 10 best ligand energies interactions and verified their interaction profile with the main TcTR sites through the AuPosSOM server (https://www.biomedicale.univ-paris5.fr/aupossom). Results and Conclusion: Finally, we analyzed some pharmacokinetics and toxicological information through the servers Aggregator Advisor (http://advisor.bkslab.org), Pred-hERG 4.0 (http://labmol.com.br/predherg) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction) which we expect will be useful in in vitro preclinical trials.</P>

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