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Mutations in DNA gyrase confer resistance to fluoroquinolones, second-line antibiotics for Mycobacterium tuberculosis infections. Identification of new agents that inhibit M. tuberculosis DNA gyrase ATPase activity is one strategy to overcome this. Here, bioisosteric designs using known inhibitors as templates were employed to define novel inhibitors of M. tuberculosis DNA gyrase ATPase activity. This yielded the modified compound R3-13 with improved drug-likeness compared to the template inhibitor that acted as a promising ATPase inhibitor against M. tuberculosis DNA gyrase. Utilization of compound R3-13 as a virtual screening template, supported by subsequent biological assays, identified seven further M. tuberculosis DNA gyrase ATPase inhibitors with IC 50 values in the range of 0.42-3.59 μM. The most active compound 1 showed an IC 50 value of 0.42 μM, 3-fold better than the comparator ATPase inhibitor novobiocin (1.27 μM). Compound 1 showed noncytotoxicity to Caco-2 cells at concentrations up to 76-fold higher than its IC 50 value. Molecular dynamics simulations followed by decomposition energy calculations identified that compound 1 occupies the binding pocket utilized by the adenosine group of the ATP analogue AMPPNP in the M. tuberculosis DNA gyrase GyrB subunit. The most prominent contribution to the binding of compound 1 to M. tuberculosis GyrB subunit is made by residue Asp79, which forms two hydrogen bonds with the OH group of this compound and also participates in the binding of AMPPNP. Compound 1 represents a potential new scaffold for further exploration and optimization as a M. tuberculosis DNA gyrase ATPase inhibitor and candidate anti-tuberculosis agent.

Mycobacterium tuberculosis protein kinase B (PknB) is essential to mycobacterial growth and has received considerable attention as an attractive target for novel anti-tuberculosis drug development. Here, virtual screening, validated by biological assays, was applied to select candidate inhibitors of M. tuberculosis PknB from the Specs compound library (www.specs.net). Fifteen compounds were identified as hits and selected for in vitro biological assays, of which three indoles ( 2 , AE-848/42799159; 4 , AH-262/34335013; 10 , AP-124/40904362) inhibited growth of M. tuberculosis H37Rv with minimal inhibitory concentrations of 6.2, 12.5, and 6.2 μg/mL, respectively. Two compounds, 2 and 10 , inhibited M. tuberculosis PknB activity in vitro , with IC 50 values of 14.4 and 12.1 μM, respectively, suggesting this to be the likely basis of their anti-tubercular activity. In contrast, compound 4 displayed anti-tuberculosis activity against M. tuberculosis H37Rv but showed no inhibition of PknB activity (IC 50 > 128 μM). We hypothesize that hydrolysis of its ethyl ester to a carboxylate moiety generates an active species that inhibits other M. tuberculosis enzymes. Molecular dynamics simulations of modeled complexes of compounds 2 , 4 , and 10 bound to M. tuberculosis PknB indicated that compound 4 has a lower affinity for M. tuberculosis PknB than compounds 2 and 10 , as evidenced by higher calculated binding free energies, consistent with experiment. Compounds 2 and 10 therefore represent candidate inhibitors of M. tuberculosis PknB that provide attractive starting templates for optimization as anti-tubercular agents.

Serine/threonine protein kinase B (PknB) is essential to Mycobacterium tuberculosis (M. tuberculosis) cell division and metabolism and a potential anti-tuberculosis drug target. Here we apply Hologram Quantitative Structure Activity Relationship (HQSAR) and three-dimensional QSAR (Comparative Molecular Similarity Indices Analysis (CoMSIA)) methods to investigate structural requirements for PknB inhibition by a series of previously described quinazoline derivatives. PknB binding of quinazolines was evaluated by molecular dynamics (MD) simulations of the catalytic domain and binding energies calculated by Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) methods. Evaluation of a training set against experimental data showed both HQSAR and CoMSIA models to reliably predict quinazoline binding to PknB, and identified the quinazoline core and overall hydrophobicity as the major contributors to affinity. Calculated binding energies also agreed with experiment, and MD simulations identified hydrogen bonds to Glu93 and Val95, and hydrophobic interactions with Gly18, Phe19, Gly20, Val25, Thr99 and Met155, as crucial to PknB binding. Based on these results, additional quinazolines were designed and evaluated in silico, with HQSAR and CoMSIA models identifying sixteen compounds, with predicted PknB binding superior to the template, whose activity spectra and physicochemical, pharmacokinetic, and anti-M. tuberculosis properties were assessed. Compound, D060, bearing additional ortho- and meta-methyl groups on its R 2 substituent, was superior to template regarding PknB inhibition and % caseum fraction unbound, and equivalent in other aspects, although predictions identified hepatotoxicity as a likely issue with the quinazoline series. These data provide a structural basis for rational design of quinazoline derivatives with more potent PknB inhibitory activity as candidate anti-tuberculosis agents., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: JAK2 inhibitors have been proposed as a new therapeutic option for thalassemia therapy. The objective of this study was to discover the key structural features for improving 2-aminopyrimidine derivatives as potential JAK2 inhibitors. Materials & methods: Quantitative structure-activity relationship (QSAR) approaches (hologram QSAR and comparative molecular similarity indices analysis), molecular dynamics simulations, binding energy calculations and pharmacokinetic predictions were employed. Results: Reliable QSAR models, binding mode and binding interactions of JAK2 inhibitors were obtained and these obtained results were used as the key information for rational design of highly potent JAK2 inhibitors. Conclusion: The concept of new potential JAK2 inhibitors integrated from the obtained results was proved, producing two newly designed compounds, D01 and D02, with potential for use as JAK2 inhibitors.

Aim: In silico screening approaches were performed to discover novel InhA inhibitors. Methods: Candidate InhA inhibitors were obtained from the combination of virtual screening and pharmacokinetic prediction. In addition, molecular mechanics Poisson-Boltzmann surface area, molecular mechanics Generalized Born surface area and WaterSwap methods were performed to investigate the binding interactions and binding energy of candidate compounds. Results: Four candidate compounds with suitable physicochemical, pharmacokinetic and antibacterial properties are proposed. The crucial interactions of the candidate compounds were H-bond, pi-pi and sigma-pi interactions observed in the InhA binding site. The binding affinity of these compounds was improved by hydrophobic interactions with hydrophobic side chains in the InhA pocket. Conclusion: The four newly identified InhA inhibitors reported in this study could serve as promising hit compounds against Mycobacterium tuberculosis and may be considered for further experimental studies.

Mycobacterium tuberculosis DNA gyrase manipulates the DNA topology using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis ; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biological assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compound library (www.specs.net). Thirty compounds were identified and selected as hits for in vitro biological assays, of which two compounds, G24 and G26 , inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concentration of 12.5 μg/mL. The two compounds inhibited DNA gyrase ATPase activity with IC 50 values of 2.69 and 2.46 μM, respectively, suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compounds G24 and G26 bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by molecular dynamics simulations followed by pharmacophore mapping analysis, showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compound lipophilicity by increasing the polarity of these tails then presents a likely route to improving the solubility and activity. Thus, compounds G24 and G26 provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.

Serum albumin (SA) is the most abundant protein in blood. SA carries a diverse range of nutrients and drugs. It has wide clinical and biochemical applications. Especially, administering human serum albumin (HSA) can increase albumin level and blood pressure in ill dogs and humans. Nonetheless, the use of HSA therapy is still controversial. Using albumin from other species is one of alternatives. Bovine serum albumin (BSA) is a homolog of HSA, but it shows different dynamics. Thus, understanding albumin properties from other species becomes crucial. Recently, the first crystal structure of canine serum albumin (CSA) has been solved. We thus employed Molecular Dynamics (MD) simulations to reveal structural and dynamic properties of CSA and BSA in comparison with HSA. The results indicate the motion of domains I and III is the key to define albumin characteristics. Among all, CSA is the most flexible. BSA and HSA are more alike in term of ligand-binding affinity. Many ligand-binding studies succeeded to employ BSA as a HSA substitute due to similar size and environment of binding pockets, however replacing HSA by BSA may fail in a dynamics-related process because of the more rigid BSA. For CSA, its properties deviate from BSA and HSA. CSA shows more flexibility and has larger and more water-exposed drug sites. Moreover, C34 on CSA is more reactive than that of BSA and HSA owing to more flexible side chain. An insight obtained can serve as a guideline for a future use of alternative albumins in clinical practice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The effect of an external electric field (EF) on the methane adsorption and its activation on iron-embedded graphene (Fe-GPs) are investigated by using the M06-L density functional method. The EF is applied in the perpendicular direction to the graphene in the range of -0.015 to +0.015 a.u. with the interval of 0.005 a.u. The effects of EF on the adsorption, transition state and product complexes of the methane activation reaction are revealed. The binding energies of methane on Fe site in Fe-GPs are increased from -12.9 to -15.3, -18.1 and -21.5 kcal/mol for the negative EF of -0.005, -0.010 and -0.015, respectively. By applying positive EF, the activation barriers for methane activation are reduced in range of 3-8 kcal/mol (around 12-31%) and the reaction energies are more exothermic. The positive EF kinetically favors the reaction compared to the system without EF. The adsorption and activation of methane on Fe-GPs can be easily tuned by adjusting the external electric field for various applications. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

The oxidation of CO by N 2 O over metal-organic framework (MOF) M 3 (btc) 2 (M = Fe, Cr, Co, Ni, Cu, and Zn) catalysts that contain coordinatively unsaturated sites has been investigated by means of density functional theory calculations. The reaction proceeds in two steps. First, the N-O bond of N 2 O is broken to form a metal oxo intermediate. Second, a CO molecule reacts with the oxygen atom of the metal oxo site, forming one C-O bond of CO 2 . The first step is a rate-determining step for both Cu 3 (btc) 2 and Fe 3 (btc) 2 , where it requires the highest activation energy (67.3 and 19.6 kcal/mol, respectively). The lower value for the iron compound compared to the copper one can be explained by the larger amount of electron density transferred from the catalytic site to the antibonding of N 2 O molecules. This, in turn, is due to the smaller gap between the highest occupied molecular orbital (HOMO) of the MOF and the lowest unoccupied molecular orbital (LUMO)  of N 2 O for Fe 3 (btc) 2 compared to Cu 3 (btc) 2 . The results indicate the important role of charge transfer for the N-O bond breaking in N 2 O. We computationally screened other MOF M 3 (btc) 2 (M = Cr, Fe, Co, Ni, Cu, and Zn) compounds in this respect and show some relationships between the activation energy and orbital properties like HOMO energies and the spin densities of the metals at the active sites of the MOFs.

First-principles gradient-corrected density functional theory electronic structure calculations of the haptotropic rearrangement of a Cr(CO)(3) unit on naphthalene and phenanthrene derivatives are reported. Coupled-cluster calibration studies of Cr(CO)(3) complexes with benzene and naphthalene derivatives confirm the accuracy of the applied Becke exchange and Perdew correlation functionals. Characteristic points on the energy hypersurface (reactants, products, intermediates, and transition states) were located for various substituents on the aromatic skeleton. It is argued that a -OH/-O(-) substituent may provide a means to steer the haptotropic shift depending on the pH value, i.e., to construct a molecular switch. In addition, the mechanism of the [3 + 2 + 1] benzannulation of chromium pentacarbonyl naphthylcarbene complexes with alkynes was investigated, and the preference of the angular benzannulation leading to phenanthrene complexes of Cr(CO)(3) over the linear benzannulation leading to corresponding anthracene complexes is explained.