Exponential consensus ranking improves the outcome in docking and receptor ensemble docking

Palacio-Rodríguez, Karen; Lans, Isaías; Cavasotto, Claudio N.; Cossio, Pilar

doi:10.1038/s41598-019-41594-3

Cited by 121 publications

(144 citation statements)

References 75 publications

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“…In the subsequent calculations, we used the relevant program of molecular dynamics, which can more accurately reflect the state of receptor-ligand complexes than molecular docking. It has proven to be able to study a wide range of phenomena related to simple and complex molecules [49]. In this study, the protein ligand complexes obtained from the molecular docking procedure were calculated by molecular dynamics.…”

Section: Discussionmentioning

confidence: 99%

Rutin, a Natural Inhibitor of IGPD Protein, Inhibits the Biofilm Formation inStaphylococcus xylosusATCC700404

Bello-Onaghise

Xing

Zhou

et al. 2019

Preprint

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Staphylococcus xylosus has been isolated from a variety of infections, and the biofilm formed by S. xylosus can help the bacteria evade the immune system of the host and cause chronic infections.Here, we dealt with this menace by establishing a highly effective drug with the ability to interfere with the process involved in the formation of biofilm in S. xylosus. IGPD has been reported to be directly involved in the formation of biofilm in Staphylococcus xylosus and it is known to be present in a variety of microorganisms. Based on this study, we developed a drug therapy targeting IGPD and at the same time interfere with the formation of biofilm in S. xylosus ABSTRACTThe biofilm of bacteria plays an important role in antibiotic resistance and chronic infection. Thus, in order to solve the problem of resistant bacteria, it is very important to find new drugs that can inhibit the formation of biofilms. In recent years, researchers have shifted their attention to natural products. As a flavonoid, rutin has been reported to have a variety of biological activities, interestingly, in this study, the inhibitory effect of rutin on the biofilm of Staphylococcus xylosus was investigated. We confirmed that rutin could effectively inhibit the biofilm formation of S. xylosus, then, for the sake of discussion on how it interferes with the biofilm formation, the interaction between rutin and imidazolyl phosphate dehydratase (IGPD) which has been identified as the key enzyme that plays a vital role in the process of biofilm formation was analyzed by molecular docking, the results showed that rutin had a strong affinity with IGPD, it occupied the hydrophobic cavity of the active center forming four hydrogen bonds and many other interactions.In addition, we proved that rutin was able to combine with IGPD using SPR technique. Therefore, we determined the enzyme activity and histidine content of IGPD, the result indicated that rutin could simultaneously inhibit the activity of IGPD and abrogate the synthesis of histidine.Interestingly, the hisB gene encoding for IGPD and IGPD in S. xylosus were also significantly inhibited when the bacterial culture was treated with rutin. Taken together, the results have provided evidence that rutin is a natural drug that has the ability to interfere with the formation of biofilm in S. xylosus. It is therefore a potential enzyme inhibitor of IGPD.

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Section: Discussionmentioning

confidence: 99%

Rutin, a Natural Inhibitor of IGPD Protein, Inhibits the Biofilm Formation inStaphylococcus xylosusATCC700404

Bello-Onaghise

Xing

Zhou

et al. 2019

Preprint

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“…Therefore, with molecular docking, it is 285 possible to screen and rank molecules from compound libraries. However, it has been 286 shown that the docking results might be system or structure dependent [43,70], possibly 287 due to algorithm-parameterization biases, which are trained over particular benchmark 288 systems. To overcome this limitation, we use a consensus strategy that combines the 289 results from different docking programs to obtain a consensus rank using a sum of 290 exponential functions (ECR method) [43].…”

Section: Ecr-docking: Exponential Consensus Ranking Of Docking Vs 280mentioning

confidence: 99%

“…However, it has been 286 shown that the docking results might be system or structure dependent [43,70], possibly 287 due to algorithm-parameterization biases, which are trained over particular benchmark 288 systems. To overcome this limitation, we use a consensus strategy that combines the 289 results from different docking programs to obtain a consensus rank using a sum of 290 exponential functions (ECR method) [43]. Below and in the Supplementary 291 Information, we explain different docking-scoring alternatives that we used to find the 292 optimal enrichment for the FMNAT-FADS ligand screening.…”

Section: Ecr-docking: Exponential Consensus Ranking Of Docking Vs 280mentioning

confidence: 99%

“…The particle mesh Ewald method was used to compute 128 long-range electrostatic force terms, and the leapfrog algorithm to propagate the Exponential consensus ranking 137 A consensus methodology was used to combine the results from different scoring 138 functions both for the docking and MD VS stages. We used an exponential consensus 139 ranking (ECR) methodology [43]. This method assigns a score p(r j i ) to each molecule i 140 for each scoring function j using an exponential function p(r j i ) = exp ( −r j i α )/α, which 141 depends on the rank of the molecule (r j i ) given by each individual docking program.…”

mentioning

confidence: 99%

“…Assays 257 were done in quadruplicate. [31], ii ) docking and exponential consensus ranking (ECR-docking) [43], iii ) MD simulations with consensus ranking -that includes a new Morse-based ligand-flexibility score-, and iv ) biological experimental binding and activity assays. At each stage, the compound library was filtered.…”

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In silicodiscovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target

Lans

Anoz-Carbonell

Palacio-Rodríguez

et al. 2020

Preprint

Self Cite

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New treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia-by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of the Corynebacterium ammoniagenes FADS. Then, it was used to find new FADS ligands from a compound library of 14,000 molecules. A small set of 17 in silico filtered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase mononucleotide of the FADS, and some of them were able to inhibit growth of three bacterial species: Corynebacterium ammoniagenes, Mycobacterium tuberculosis, and Streptococcus pneumoniae, where the former two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.April 16, 2020 1/22Developing cures for antimicrobial-resistant microorganisms is a pressing necessity. Addressing this problem requires the discovery of novel therapeutic targets -for example, bacterial proteins with no human homologues-and the development of cost-effective drug screening protocols. In this work, we tackled the problem on both sides. We developed an efficient and successful integrative computational protocol for screening inhibitory-molecules for unexplored targets. We used it to discover five novel inhibitors of flavin-adenine dinucleotide synthase (FADS), a promising protein target of pathogens causing tuberculosis and pneumonia. 7 and effective way to increase the chances of success of the drug-screening pipeline is 8 through the implementation of efficient virtual screening (VS) protocols. These 9 methods provide powerful tools to reduce the costs of drug discovery by reducing the 10 number of compounds to be tested in experimental trial...

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Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS‐CoV‐2 main protease

Carvalho,

Souza,

Tizziani

et al. 2024

Archiv der Pharmazie

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The present work reports the inhibitory effect of amides derived from gallic acid (gallamides) against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease (Mpro), along with cytotoxicity evaluation and molecular docking studies. In addition to gallamides, other relevant compounds were also synthesized and evaluated against Mpro, making a total of 25 compounds. Eight compounds presented solubility issues during the inhibitory assay and one showed no inhibitory activity. Compounds 3a, 3b, and 3f showed the highest enzymatic inhibition with IC50 = 0.26 ± 0.19 µM, 0.80 ± 0.38 µM, and 2.87 ± 1.17 µM, respectively. Selenogallamide 6a exhibited IC50 values of 5.42 ± 2.89 µM and a comparison with its nonselenylated congener 3c shows that the insertion of the chalcogen moiety improved the inhibitory capacity of the compound by approximately 10 times. Regarding the cellular toxicity in THP‐1 and Vero cells, compounds 3e and 3g, showed moderate cytotoxicity in Vero cells, while for THP‐1 both were nontoxic, with CC50 > 150 µM. Derivative 3d showed moderate cytotoxicity against both cell lines, whereas 6d was moderatly toxic to THP‐1. Other compounds analyzed do not induce substantial cellular toxicity at the concentrations tested. The molecular docking results for compounds 3a, 3b, and 3f show that hydrogen bonding interactions involving the hydroxyl groups (OH) of the gallate moiety are relevant, as well as the carbonyl group.

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Exponential consensus ranking improves the outcome in docking and receptor ensemble docking

Cited by 121 publications

References 75 publications

Rutin, a Natural Inhibitor of IGPD Protein, Inhibits the Biofilm Formation inStaphylococcus xylosusATCC700404

Rutin, a Natural Inhibitor of IGPD Protein, Inhibits the Biofilm Formation inStaphylococcus xylosusATCC700404

In silicodiscovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target

Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS‐CoV‐2 main protease

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