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Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361017


Glycogen synthase kinase-3 beta (GSK-3ß) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3ß allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3ß allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3ß allosteric modulators.

Sítio Alostérico , Glicogênio Sintase Quinase 3 beta/química , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/farmacologia , Regulação Alostérica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Fármacos Neuroprotetores/química , Ligação Proteica
J Biomol Struct Dyn ; : 1-23, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33427075


Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.

Pharmaceuticals (Basel) ; 13(9)2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32858871


The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = -11.0 kcal/mol), LMQC36 (∆G = -10.6 kcal/mol), and LMQC50 (∆G = -10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = -10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = -45.31 kcal/mol; LMQC72: ΔGbind = -38.58 kcal/mol; LMQC36: ΔGbind = -36.10 kcal/mol; and LMQC50: ΔGbind = -39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991684


Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.

Anti-Inflamatórios não Esteroides/química , Benzoatos/química , Simulação por Computador , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/química , Ibuprofeno/química , Simulação de Acoplamento Molecular , Propionatos/química , Animais , Humanos , Camundongos , Ratos
Pharmaceuticals (Basel) ; 12(1)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871010


Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, responsible for 1.5 million documented deaths in 2016. The increase in reported cases of M. tuberculosis resistance to the main drugs show the need for the development of new and efficient drugs for better TB control. Based on these facts, this work aimed to use combined in silico techniques for the discovery of potential inhibitors to ß-ketoacyl-ACP synthase (MtKasA). Initially compounds from natural sources present in the ZINC database were selected, then filters were sequentially applied by virtual screening, initially with pharmacophoric modeling, and later the selected compounds (based on QFIT scores) were submitted to the DOCK 6.5 program. After recategorization of the variables (QFIT score and GRID score), compounds ZINC35465970 and ZINC31170017 were selected. These compounds showed great hydrophobic contributions and for each established system 100 ns of molecular dynamics simulations were performed and the binding free energy was calculated. ZINC35465970 demonstrated a greater capacity for the KasA enzyme inhibition, with a ΔGbind = -30.90 kcal/mol and ZINC31170017 presented a ΔGbind = -27.49 kcal/mol. These data can be used in other studies that aim at the inhibition of the same biological targets through drugs with a dual action.

Molecules ; 24(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609687


A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13⁻15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13⁻15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.

Fenilbutazona/química , Fenilbutazona/farmacologia , Descoberta de Drogas/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fenilbutazona/efeitos adversos , Fenilbutazona/toxicidade , Relação Estrutura-Atividade