Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Tosso, Rodrigo D.; Andújar, Sebastián Antonio; Gutiérrez, Lucas; Angelina, Emilio; Rodríguez, Ricaurte; Nogueras, Manuel; Baldoni, Héctor A.; Suvire, Fernando D.; Cobo, Justo; Enriz, Ricardo D.

doi:10.1021/ci400178h

Cited by 59 publications

(66 citation statements)

References 86 publications

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“…We recently reported that the charge density value at the bond critical point (ρ(r b )), which is a descriptor of the strength of the different bonds, can be used to quantify the affinity of a ligand to form a complex ligand-receptor [67,70]. We have analyzed the complexes obtained for the three compounds reported here 2 , 3 and 4 using this type of analysis and also included compound PF543 for comparison.…”

Section: Resultsmentioning

confidence: 99%

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

Vettorazzi

Angelina

Lima

et al. 2017

European Journal of Medicinal Chemistry

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Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphin-gosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b] pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

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Section: Resultsmentioning

confidence: 99%

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

Vettorazzi

Angelina

Lima

et al. 2017

European Journal of Medicinal Chemistry

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“…MD trajectories were projected along the first PC (PC1) and frames with extreme values of projection were selected for subsequent charge density topological analysis using QTAIM . This analysis has been very useful for evaluating the interactions in bio‐molecular systems …”

Section: Computational Detailsmentioning

confidence: 99%

Flap‐site Fragment Restores Back Wild‐type Behaviour in Resistant Form of HIV Protease

Luchi

Angelina

Bogado

et al. 2018

Molecular Informatics

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HIV-1 protease (HIV-PR) performs a vital step in the virus life cycle which makes it an excellent target for drug therapy. However, due to the error-prone of HIV reverse transcriptase, mutations in HIV-PR often occur, inducing drug-resistance to inhibitors. Some HIV-PR mutations can make the flaps of the enzyme more flexible thus increasing the flaps opening rate and inhibitor releasing. It has been shown that by targeting novel binding sites on HIV-PR with small molecules, it is possible to alter the equilibrium of flap conformational states. A previous fragment-based crystallographic screen have found two novel binding sites for small fragments in the inhibited, closed form of HIV-PR, termed flap and exo sites. While these experiments were performed in wild type HIV-PR, it still remains to be proven whether these small fragments can stabilize the closed conformation of flaps in resistant forms of the enzyme. Here we performed Molecular Dynamics simulations of wild type and mutant form of HIV-PR bound to inhibitor TL-3. Simulations show that on going from wild type to 6X mutant the equilibrium shifts from closed to semi-open conformation of flaps. However, when fragment Br6 is placed at flap site of mutant form, the enzyme is restored back to closed conformation. This finding supports the hypothesis that allosteric inhibitors, together with active site inhibitors could increase the number of point mutations necessary for appreciable clinical resistance to AIDS therapy.

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“…[1][2][3] Baquiloprim (BQP), trimethoprim (TMP), ormetoprim (OMP) and diaveridine (DVD) have been used in human and veterinary medicines for the treatment and prevention of disease since many years. [1][2][3] Baquiloprim (BQP), trimethoprim (TMP), ormetoprim (OMP) and diaveridine (DVD) have been used in human and veterinary medicines for the treatment and prevention of disease since many years.…”

Section: Introductionmentioning

confidence: 99%

Two generation reproduction and teratogenicity studies of feeding diaveridine in Wistar rats

Wang¹,

Ihsan

et al. 2015

Toxicol. Res.

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Diaveridine (DVD), belonging to the class of compounds called diaminopyrimidines, has been widely used as a bacteriostatic agent. To evaluate the reproductive toxicity and teratogenic potential of DVD, different concentrations of DVD were administered to Wistar rats by feeding diets containing 0, 23, 230, 1150 and 2000 mg kg −1 of DVD. Each group consisting of 18 males and 25 females (F 0 ) was treated with different concentrations of DVD through a 13-week period prior to mating, during mating, gestation, parturition and lactation. At weaning, 20 males and 25 females of F 1 generation weanlings per group were selected randomly as parents for the F 2 generation. The selected F 1 weanlings were exposed to the same diet and treatment as their parents. In the F 0 and F 1 generation of the 1150 and 2000 mg kg −1 diet groups, the body weight, feed efficiency, weight gain of pregnant rats, litter and average number of live fetuses and fetus body weight significantly decreased. In the highest dose group, uterine wall contraction, narrow uterine cavity and uterine tumor were observed. Combined with the 2nd generation reproduction test to investigate the teratogenic toxicity of DVD in Wistar rats, the pregnant rats were subjected to caesarean section on the 20th gestational day for examination. For the 1150 and 2000 mg kg −1 groups, the litter weights, body weights, body length, tail length of fetus and number of viable fetuses significantly decreased. There were no obvious external, skeletal and visceral effects in all the groups. The noobserved-adverse-effect level for reproduction/development toxicity of DVD was 23 mg kg −1 diet (about 2.3-2.8 mg per kg b.w. per day).

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Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Cited by 59 publications

References 86 publications

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

Flap‐site Fragment Restores Back Wild‐type Behaviour in Resistant Form of HIV Protease

Two generation reproduction and teratogenicity studies of feeding diaveridine in Wistar rats

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