Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro) Pedro Henrique R. de A. Azevedo, Priscila G. Camargo, Larissa E. C. Constant, Stephany da S. Costa, Celimar Sinézia Silva, et al. Scientific Reports, 2024 COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.
In silico drug repurposing by combining machine learning classification model and molecular dynamics to identify a potential OGT inhibitor Pedro Henrique Rodrigues de Alencar Azevedo, Bruna Rachel de Britto Peçanha, Luiz Augusto Pinheiro Flores-Junior, Tatiana Fialho Alves, Luiza Rosaria Sousa Dias, et al. Journal of Biomolecular Structure and Dynamics, 2024 O-linked N-acetylglucosamine (O-GlcNAc) is a unique intracellular post-translational glycosylation at the hydroxyl group of serine or threonine residues in nuclear, cytoplasmic and mitochondrial proteins. The enzyme O-GlcNAc transferase (OGT) is responsible for adding GlcNAc, and anomalies in this process can lead to the development of diseases associated with metabolic imbalance, such as diabetes and cancer. Repurposing approved drugs can be an attractive tool to discover new targets reducing time and costs in the drug design. This work focuses on drug repurposing to OGT targets by virtual screening of FDA-approved drugs through consensus machine learning (ML) models from an imbalanced dataset. We developed a classification model using docking scores and ligand descriptors. The SMOTE approach to resampling the dataset showed excellent statistical values in five of the seven ML algorithms to create models from the training set, with sensitivity, specificity and accuracy over 90% and Matthew's correlation coefficient greater than 0.8. The pose analysis obtained by molecular docking showed only H-bond interaction with the OGT C-Cat domain. The molecular dynamics simulation showed the lack of H-bond interactions with the C- and N-catalytic domains allowed the drug to exit the binding site. Our results showed that the non-steroidal anti-inflammatory celecoxib could be a potentially OGT inhibitor.
Trypanocidal activity of new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives: Synthesis, in vitro and in vivo studies Joana L.S. Ribeiro, Júlio C.A.V. Soares, Gisele B. Portapilla, Maiara V. Providello, Camilo H.S. Lima, et al. Bioorganic and Medicinal Chemistry, 2021 Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
Biological evaluation and molecular modeling of peptidomimetic compounds as inhibitors for O-GlcNAc transferase (OGT) Suraby O. Albuquerque, Thalita G. Barros, Luiza R.S. Dias, Camilo H. da S. Lima, Pedro H.R. de A. Azevedo, et al. European Journal of Pharmaceutical Sciences, 2020 The vital enzyme O-linked β-N-acetylglucosamine transferase (OGT) catalyzes the O-GlcNAcylation of intracellular proteins coupling the metabolic status to cellular signaling and transcription pathways. Aberrant levels of O-GlcNAc and OGT have been linked to metabolic diseases as cancer and diabetes. Here, a new series of peptidomimetic OGT inhibitors was identified highlighting the compound LQMed 330, which presented better IC50 compared to the most potent inhibitors found in the literature. Molecular modeling study of selected inhibitors into the OGT binding site provided insight into the behavior by which these compounds interact with the enzyme. The results obtained in this study provided new perspectives on the design and synthesis of highly specific OGT inhibitors.
Biological activities of [1,2,4]triazolo[1,5-a]pyrimidines and analogs Sergio Pinheiro, Erick M. C. Pinheiro, Estela M. F. Muri, Jaqueline C. Pessôa, Mayara A. Cadorini, et al. Medicinal Chemistry Research, 2020 The [1,2,4]triazolo[1,5-a]pyrimidines (TPs) comprise an important class of non-naturally occurring small molecules that aroused the interest of researches. This scaffold is present in diverse important structures in agriculture and medicinal chemistry, such as antibacterial, antifungal, antiviral, antiparasitic, and anticancer. As over the decades the development of the chemistry and application of 1,2,4-triazolo[1,5-a]pyrimidines has continued and even accelerated, in this review, we thoroughly discussed the applications of TPs in both agriculture and medicinal chemistry highlighting the significance of this nucleus.
2H-1,2,3-Triazole-chalcones as novel cytotoxic agents against prostate cancer Sergio Pinheiro, Jaqueline C. Pessôa, Erick M.C. Pinheiro, Estela M.F. Muri, Eclair Venturini Filho, et al. Bioorganic and Medicinal Chemistry Letters, 2020 Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.
Anti-trypanosoma cruzi activity and molecular docking studies of 1H-pyrazolo[3, 4-b]pyridine derivatives Camilo Henrique da Silva Lima, Júlio César de Araujo Vanelis Soares, Joana Lucius de Sousa Ribeiro, Estela Maris Freitas Muri, Sérgio de Albuquerque, et al. Letters in Drug Design and Discovery, 2020 Background: Untargeted studies led to the development of some pyrazolopyridine derivatives for the antiparasitic profile, particularly the derivatives containing the structural carbohydrazide subunit. In this work, we proceeded in the biological screening of 27 N’- (substitutedphenylmethylene)- 4-carbohydrazide-3-methyl-1-phenyl-1H-pyrazolo[3, 4-b]pyridine derivatives against T. cruzi as well as the cytotoxic evaluation. To obtain more information about the trypanocidal activity of this class of compounds, we carried out molecular docking simulations to get an insight into putative targets in T. cruzi. Methods: The assays were evaluated against both trypomastigote and amastigote forms of T. cruzi and cytotoxicity assays on LLCMK2 cells. The predominant conformational compounds were analyzed and molecular docking simulations performed. Results: The results from trypanocidal activity screening of this series showed that just the compounds with phenyl group at C-6 position exhibited activity and the N’-4-hydroxyphenylmethylene derivative presented the best profile against both trypomastigote and amastigote forms of T. cruzi. Docking simulation results showed that this compound has a binding affinity with both CYP51 and cruzain targets of T. cruzi. Conclusion: Our results indicate that the hydroxyl substituent at the N’-substituted-phenylmethylene moiety and the phenyl ring at C-6 of 1H-pyrazolo[3,4-b]pyridine system are relevant for the trypanocidal activity of this class of compounds. Also, docking simulations showed that activity presented can be related to more than one target of the parasite.
