Rational Approach toward COVID-19's Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis.

This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from -6.2 to -9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein-ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.

Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2.

When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts' angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein's crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport®. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of -8.645 kcal·mol-1, which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC50 values (ranging from 0.459 to 2.371 µM) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach.

Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer's disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the hAChE B site of the human acetylcholinesterase (hAChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential hAChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for hAChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches.

Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson's correlation for the construction of quantitative structure-activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (-log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski's rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches.

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.

Molecular Electronics Including Temperature Effects Based on Dyes Pigments.

In this work we used the Density Functional Theory to study the thermodynamic properties from Brazilein (BZE) and Brazilin (BZI) molecules, main pigments responsible for the red color from Brazil wood. We did a comparison between the two dyes to then know which dye has better resistance to temperature (T ) and external electric field (E) values, aiming their potential to possible applications in solar cells, as excitons trainers. We have found that the BZE molecule becomes less stable after a temperature known as degradation temperature, and therefore enters oxidation state. However, BZE is more stable and more resistant to high temperatures. With respect to the applied external electric field, we find that BZE is more reactive to almost all the applied electric fields, thus more easily converted into energy in the form of electrical work.

Sensors Using the Molecular Dynamics of Explosives in Carbon Nanotubes Under External Uniform Electric Fields.

Possessing a simulated sensor device to identify explosives is of extreme interest to the area of public security to fight against terrorism. In light of this, a carbon armchair nanotube was modeled under the action of an external, longitudinal and uniform electric field at an initial temperature of 1 mK simulation, causing the explosive molecules under analysis to rotate through the carbon nanotube, due to an evanescent effect generated from the action of an electric current and magnetic field induced in this system, and thus behaving as a selective temperature sensor and spinning radius for the molecules. For this, molecular dynamics was used to study the physicochemical properties of the molecules' interactions with a carbon nanotube. The following physical properties, as well as the kinetic, potential, and total energy were calculated for the 2,4,6-trinitrotoluene (TNT), triacetone triperoxide (TATP), hexogen (RDX), hexamethylene triperoxide diamine (HMTD), octogen (HMX) and pentaerythritol tetranitrate (PETN) explosives: thermodynamic conditions such as temperature; entropy variation; and distance between the molecules' center of mass from an armchair type carbon nanotube.

Removal of Organic Pollutants Benzene and Phenol Using Nanofiltration: A Molecular Dynamics Study.

Population growth has resulted in an increased demand for clean water. It is known that chemical pollutants such as phenol and benzene often make water unfit for consumption, and can be responsible for the appearance of diseases such as cancer. In this sense, studies aimed at decontaminating water are still necessary. In this study, molecular dynamics simulations were performed to evaluate the abilities of activated charcoal structures to adsorb benzene and phenol; the results of which were evaluated on the basis of root mean square deviations for all systems. The data were collected from the molecular dynamics (MD) trajectories and edited with the grace plotting tool. Visual molecular dynamics software was used to visualize the MD paths, and images were created using the UCSF chimera software. The results show that activated charcoal are viable alternatives for water decontamination by nanofiltration.

A review on mycogenic metallic nanoparticles and their potential role as antioxidant, antibiofilm and quorum quenching agents.

The emergence of antimicrobial resistance among biofilm forming pathogens aimed to search for the efficient and novel alternative strategies. Metallic nanoparticles have drawn a considerable attention because of their significant applications in various fields. Numerous methods are developed for the generation of these nanoparticles however, mycogenic (fungal-mediated) synthesis is attractive due to high yields, easier handling, eco-friendly and being energy efficient when compared with conventional physico-chemical methods. Moreover, mycogenic synthesis provides fungal derived biomolecules that coat the nanoparticles thus improving their stability. The process of mycogenic synthesis can be extracellular or intracellular depending on the fungal genera used and various factors such as temperature, pH, biomass concentration and cultivation time may influence the synthesis process. This review focuses on the synthesis of metallic nanoparticles by using fungal mycelium, mechanism of synthesis, factors affecting the mycosynthesis and also describes their potential applications as antioxidants and antibiofilm agents. Moreover, the utilization of mycogenic nanoparticles as quorum quenching agent in hampering the bacterial cell-cell communication (quorum sensing) has also been discussed.

Green Surfactants (Biosurfactants): A Petroleum-Free Substitute for Sustainability-Comparison, Applications, Market, and Future Prospects.

Surfactants are a group of amphiphilic molecules (i.e., having both hydrophobic and hydrophilic domains) that are a vital part of nearly every contemporary industrial process such as in agriculture, medicine, personal care, food, and petroleum. In general surfactants can be derived from (i) petroleum-based sources or (ii) microbial/plant origins. Petroleum-based surfactants are obvious results from petroleum products, which lead to petroleum pollution and thus pose severe problems to the environment leading to various ecological damages. Thus, newer techniques have been suggested for deriving surfactant molecules and maintaining environmental sustainability. Biosurfactants are surfactants of microbial or plant origins and offer much added advantages such as high biodegradability, lesser toxicity, ease of raw material availability, and easy applicability. Thus, they are also termed "green surfactants". In this regard, this review focused on the advantages of biosurfactants over the synthetic surfactants produced from petroleum-based products along with their potential applications in different industries. We also provided their market aspects and future directions that can be considered with selections of biosurfactants. This would open up new avenues for surfactant research by overcoming the existing bottlenecks in this field.

Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach.

Alzheimer's disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results.

Identification of a Novel Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase: In Vitro and In Silico Studies.

The enhancement of cholinergic functions via acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition is considered a valuable therapeutic strategy for the treatment of Alzheimer's disease. This study aimed to evaluate the in vitro effect of ZINC390718, previously filtered using computational approaches, on both cholinesterases and to characterize, using a molecular dynamics (MD) simulation, the possible binding mode of this compound inside the cholinesterase enzymes. The in vitro cytotoxicity effect was also investigated using a primary astrocyte-enriched glial cell culture. ZINC390718 presented in vitro dual inhibitory activity against AChE at a high micromolar range (IC50 = 543.8 µM) and against BuChE (IC50 = 241.1 µM) in a concentration-dependent manner, with greater activity against BuChE. The MD simulation revealed that ZINC390718 performed important hydrophobic and H-bond interactions with the catalytic residue sites on both targets. The residues that promoted the hydrophobic interactions and H-bonding in the AChE target were Leu67, Trp86, Phe123, Tyr124, Ser293, Phe295, and Tyr341, and on the BuChE target, they were Asp70, Tyr332, Tyr128, Ile442, Trp82, and Glu197. The cytotoxic effect of Z390718, evaluated via cell viability, showed that the molecule has low in vitro toxicity. The in vitro and in silico results indicate that ZINC390718 can be used as chemotype for the optimization and identification of new dual cholinesterase inhibitors.

Pharmacological Characteristics of the Hydroethanolic Extract of Acmella oleracea (L) R. K. Jansen Flowers: ADME/Tox In Silico and In Vivo Antihypertensive and Chronic Toxicity Evaluation.

Acmella oleracea (L.) R. K. Jansen, popularly known as jambu in Northern Brazil, is widely used in folk medicine and local cuisine. Its consumption in different ways reinforces the need for safety assessments. In this study, the major compounds found in the hydroethanolic extract of A. oleracea flowers (EHFAO) were characterized by ultra-performance liquid mass spectrometry (UHPLC-ESI-QTOF-MS/MS). The effects of oral administration of 100/mg/kg of EHFAO extract over 60 days in male spontaneously hypertensive (SHR) and Wistar (WR) rats and the in silico ADME/Tox predictions, lipophilicity, and water solubility were accomplished for the compounds identified. Spilanthol was detected as the foremost major compound at a concentration of 97.7%, followed by 1.53% scopoletin and 0.77% d-limonene. The treatment with EHFAO did not alter the animals´ weight over the studied period. Moderate alterations were observed solely in the hepatic enzymes AST (WR = 97 UI/L and SHR = 150 UI/L ∗ p < 0.05) and ALT (WR = 55 UI/L and SHR = 95 UI/L ∗ p < 0.05), while no relevant histopathological alterations were found. The in-silico study confirmed the in vivo findings, as the identified compounds were considered highly bioactive orally, due to their drug similarity profiles, adequate lipid solubility, bioavailability, and pharmacokinetics. Therefore, the chronic treatment with EHFAO was found safe at the concentration of 100/mg/kg, with no interference in the blood pressure levels neither appreciable toxic effects.

Hierarchical Virtual Screening of Potential New Antibiotics from Polyoxygenated Dibenzofurans against Staphylococcus aureus Strains.

Staphylococcus aureus is a microorganism with high morbidity and mortality due to antibiotic-resistant strains, making the search for new therapeutic options urgent. In this context, computational drug design can facilitate the drug discovery process, optimizing time and resources. In this work, computational methods involving ligand- and structure-based virtual screening were employed to identify potential antibacterial agents against the S. aureus MRSA and VRSA strains. To achieve this goal, tetrahydroxybenzofuran, a promising antibacterial agent according to in vitro tests described in the literature, was adopted as the pivotal molecule and derivative molecules were considered to generate a pharmacophore model, which was used to perform virtual screening on the Pharmit platform. Through this result, twenty-four molecules were selected from the MolPort® database. Using the Tanimoto Index on the BindingDB web server, it was possible to select eighteen molecules with greater structural similarity in relation to commercial antibiotics (methicillin and oxacillin). Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the eighteen most similar molecules, showed that only three exhibited desired properties (LB255, LB320 and LB415). In the molecular docking study, the promising molecules LB255, LB320 and LB415 showed significant values in both molecular targets. LB320 presented better binding affinity to MRSA (-8.18 kcal/mol) and VRSA (-8.01 kcal/mol) targets. Through PASS web server, the three molecules, specially LB320, showed potential for antibacterial activity. Synthetic accessibility (SA) analysis performed on AMBIT and SwissADME web servers showed that LB255 and LB415 can be considered difficult to synthesize and LB320 is considered easy. In conclusion, the results suggest that these ligands, particularly LB320, may bind strongly to the studied targets and may have appropriate ADME/Tox properties in experimental studies.

Methoxylated flavonols from Vellozia dasypus Seub ethyl acetate active myeloperoxidase extract: in vitro and in silico assays.

This study aimed to evaluate the effect of a methoxylated fraction from Vellozia dasypus Seub on myeloperoxidase (MPO)-chlorinating activity and subsequent in silico assays for binding profile prediction. Therefore, the ethyl acetate extract of aerial parts from Vellozia dasypus Seub was fractionated on open-column chromatography containing SiO2 and eluted with solvent in crescent polarity to yield a fraction with a mixture of flavonols quercetin 3-O-methyl ether (1) and 6-C-methyl quercetin 3-O-methyl ether (2). Their chemical structures were proposed by HPLC coupled to photodiode array (HPLC-DAD) and mass spectrometer using electrospray ionization multistage analysis (HPLC-MS/MS). The fraction enriched with compounds 1 and 2 inhibited more efficiently the in vitro MPO-chlorinating activity (IC50 = 40 µg/mL) than the ethyl acetate extract (IC50 = 64.0 µg/mL). Molecular docking studies revealed that these compounds interact with MPO active pocket similarly to trifluoromethyl-substituted aromatic hydroxamate, a well-known MPO inhibitor, co-crystallized at the MPO binding site (PDB ID: 4C1M). Molecular dynamics trajectories confirmed that these two molecules interact with the MPO binding site with a similar energetic pattern when compared to the crystallographic ligand. Taken together, these data expand the sources of phenolic natural compounds that may be further investigated against inflammation-related diseases. Communicated by Ramaswamy H. Sarma.

Inflammasome NLRP3 activation induced by Convulxin, a C-type lectin-like isolated from Crotalus durissus terrificus snake venom.

Convulxin (CVX), a C-type lectin-like protein isolated from the venom of the snake species, Crotalus durissus terrificus, stimulates platelet aggregation by acting as a collagen receptor agonist for glycoprotein VI found in the platelets. The effect of CVX on platelets has been studied, but its effect on human peripheral blood mononuclear cells (PBMCs) remains unclear. Given the significance of PBMCs in inflammation, this study explored the effect of CVX on PBMCs, specifically regarding NLRP3 inflammasome activation by assessing cell viability, ability to induce cell proliferation, reactive oxygen species (ROS) and nitric oxide production, interleukin (IL)-2 and IL-10 secretion, NLRP3 complex activation, and the role of C-type lectin-like receptors (CTLRs) in these. CVX was not toxic to PBMCs at the investigated concentrations and did not increase PBMC growth or IL-2 release; however, CVX induced IL-10 release and ROS generation via monocyte activation. It also activated the NLRP3 complex, resulting in IL-1ß induction. Furthermore, the interaction between CVX and Dectin-2, a CTLR, induced IL-10 production. CVX interaction with CTLR has been demonstrated by laminarin therapy. Because of the involvement of residues near the Dectin-2 carbohydrate-recognition site, the generation of ROS resulted in inflammasome activation and IL-1ß secretion. Overall, this work helps elucidate the function of CVX in immune system cells.

Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations.

Glioblastoma is an aggressive primary tumor of the central nervous system (CNS). Is the most aggressive among infiltrative gliomas arising from the CNS. This tumor has low patient survival rate and several studies aiming at developing new drugs have increased. Patients with this cancer type face significant morbidity and mortality. This study evaluated the antineoplastic activity of synthetic chalcones (3a-3f) using in vitro glioblastoma models and molecular modeling. Cytotoxicity assay showed that Astrocitoma Hospital Ofir Loyola No 1 (AHOL1) and Uppsala 87 neoplastic glioblastoma lines (U87) cellular viability were significantly reduced compared to Healthy human fibroblasts cell lines (AN27) when exposed to chalcones. Interaction with the serine amino acid was present in the most promising and the reference binder docking, suggesting its importance inhibiting cell growth. Comparative analysis between the reference ligands and the molecules showed that the amino acid LYS352 present in all fittings, suggesting that this is the main amino acid for interaction with tubulin and are consistent with those in cytotoxicity assay, suggesting antineoplastic potential in glioblastoma. Long trajectory molecular dynamics studies were also carried out in order to investigate stability and conformations amongst the chalcones bound tubulin as well, in comparison to doxorubicin (here used as control), however future studies are needed to further assess the mechanism of inhibition of chalcones used in this investigation.Communicated by Ramaswamy H. Sarma.

Molecular modeling approaches of selective adenosine receptor type 2A agonists as potential anti-inflammatory drugs.

Adenosine A2A receptor (A2AR) is the predominant receptor in immune cells, where its activation triggers cAMP-mediated immunosuppressive signaling and the underlying inhibition of T cells activation and T cells-induced effects mediated by cAMP-dependent kinase proteins mechanisms. In this study, were used ADME/Tox, molecular docking and molecular dynamics simulations to investigate selective adenosine A2AR agonists as potential anti-inflammatory drugs. As a result, we obtained two promising compounds (A and B) that have satisfactory pharmacokinetic and toxicological properties and were able to interact with important residues of the A2AR binding cavity and during the molecular dynamics simulations were able to keep the enzyme complexed.Communicated by Ramaswamy H. Sarma.

Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach.

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.

Molecular dynamics simulation and binding free energy studies of novel leads belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis Polyketide Synthase 13.

In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔGbind) obtained for the Tam16 lead molecule was of -51.43 kcal/mol. When comparing this result with the ΔGbind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC50 = 0.19 µM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.