A dynamic niching genetic algorithm strategy for docking highly flexible ligands

Magalhães, Camila S. de; Almeida, Diogo Marinho; Barbosa, Hélio J. C.; Dardenne, Laurent E.

doi:10.1016/j.ins.2014.08.002

Cited by 156 publications

(158 citation statements)

References 29 publications

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“…34 These analyses support our initially proposed binding mode based on the superposition of tozasertib in complex with Aurora A and TBK1. According to our assumption that the pyrazole moiety accounts for the formation of hydrogen interactions to the backbone amides within the hinge region a similar binding mode was observed.…”

Section: Acs Chemical Biologysupporting

confidence: 82%

Identification and Further Development of Potent TBK1 Inhibitors

et al. 2014

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The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules.

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Section: Acs Chemical Biologysupporting

confidence: 82%

Identification and Further Development of Potent TBK1 Inhibitors

et al. 2014

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“…towards substrate 5 b, a molecular docking study of 5 a-c in the catalytic site of this enzyme was performed using the Dockthor program. [48][49][50] The configurations obtained after 30 docking runs per ligand with 3 million evaluations per run were subjected to statistical analysis based not only on the energy but also considering the maximum distance of 4.5 between the C4N carbon atom of the nicotinamide ring and the carbon atom of the carbonyl group of the substrate. As a result, for 5 a and 5 c 83 and 80 % of the configurations, respectively, were oriented in such a way that the hydride transfer would occur on the re face.…”

Section: Resultsmentioning

confidence: 99%

Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

et al. 2015

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E. coli cells that contain overexpressed alcohol dehydrogenases (ADHs) were screened as biocatalysts for the stereoselective reduction of chloroketones 5 a–d, the corresponding halohydrins 6 a–d of which are building blocks in the synthesis of antiretroviral drugs. Among them, ADH from Sphingobium yanoikuyae was found to reduce chloroketone 5 c with a high stereoselectivity (90 % de) and conversion (85 %) to furnish threo halohydrin (R,S)‐6 c. ADH from Ralstonia sp. (RasADH) was able to reduce 5 a and 5 b with complementary diastereoselectivity to provide access to both threo and erythro halohydrins through “substrate‐based” stereocontrol. The RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % diastereomeric excess (de) and (S,S)‐6 b with 95 % conversion and 86 % de. Molecular modeling studies showed that 5 b, which features a carboxybenzyl protecting group, is able to bind to the enzyme catalytic site in an “inverted” mode in comparison to tert‐butyloxycarbonyl‐ and methyloxycarbonyl‐protected substrates 5 a and 5 c, which sheds light on the observed switching of the stereopreference. RasADH‐catalyzed reductions were optimized to provide (R,S)‐6 a with 98 % conversion and 84 % de and (S,S)‐6 b with 95 % conversion and 86 % de.

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“…With the prepared PDE5 protein structures (crystallographic and from MD trajectories) and optimized compounds, the DockThor program was adopted for molecular docking calculations (online platform version https://dockthor.lncc.br/v2/#). DockThor is a receptor-ligand docking server, which employs a multiple solution genetic algorithm to predict the best structures and their energies, considering a flexible ligand-rigid receptor model and the MMFF94S force field [42]. The genetic algorithm implemented in DockThor performs one million cycles (number of evaluations) to generate new individuals (structures) from randomly picked parents (initial population).…”

Section: Molecular Docking Protocolmentioning

confidence: 99%

In Silico Mapping of Essential Residues in the Catalytic Domain of PDE5 Responsible for Stabilization of Its Commercial Inhibitors

2019

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Phosphodiesterase type 5 (PDE5) is an important enzyme associated with the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). Due to the relevant role of second messenger cGMP as a mediator in many physiological processes, efforts have been converged to find a safe pharmacological approach, seeking a specific, selective and potent inhibitor of the PDE5 enzyme. There are five commercial drugs with potential for clinical use: tadalafil, sildenafil, avanafil, udenafil and vardenafil. Here, we applied molecular modeling to obtain different profiles of protein–ligand interactions by adopting distinct PDE5 structures, specifically PDBid:1XOZ and two extracted from molecular dynamics (MD) simulations. The results generated by molecular docking showed several possibilities for inhibitor interactions with the catalytic pocket. Tadalafil, sildenafil and vardenafil were clearly stabilized by Gln817 via a well-oriented hydrogen bond. Another set of different interactions, such as polar, hydrophobic, π-stacking, metal–ligand and electrostatic, were responsible for accommodating avanafil and udenafil. All of the ligands are discussed in detail with consideration of the distinct protein structures, and a profile of the probability of residue–ligand contact is suggested, with the most frequently observed being: Tyr612, His613, Ser661, Thr723, Asp724, Asp764, Leu765, Val782 and Phe786. The molecular interactions displayed herein confirm findings achieved by previous authors and also present new contacts. In addition, the discussion can help researchers obtain a molecular basis for planning new selective PDE5 inhibitors, as well as explain an inhibitor’s experimental assays by considering the specific interactions occurring at the catalytic site.

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A dynamic niching genetic algorithm strategy for docking highly flexible ligands

Cited by 156 publications

References 29 publications

Identification and Further Development of Potent TBK1 Inhibitors

Identification and Further Development of Potent TBK1 Inhibitors

Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs

In Silico Mapping of Essential Residues in the Catalytic Domain of PDE5 Responsible for Stabilization of Its Commercial Inhibitors

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