PLS and shape-based similarity analysis of maleimides – GSK-3 inhibitors

Crisan, Luminita; Pacureanu, Liliana; Avram, Sorin; Bora, Alina; Avram, Speranța; Kurunczi, Ludovic

doi:10.3109/14756366.2013.833196

Cited by 11 publications

(7 citation statements)

References 69 publications

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“…The 3D similarity search methods are based on the supposition that molecules with similar structures may have similar activity [ 54 ]. The ROCS algorithm [ 29 , 30 , 55 , 56 ] searches similar compounds with a query molecule and recovers them based on the molecular shape.…”

Section: Resultsmentioning

confidence: 99%

Small Molecules of Natural Origin as Potential Anti-HIV Agents: A Computational Approach

Crisan

Bora

2021

Life

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The human immunodeficiency virus type 1 (HIV-1), one of the leading causes of infectious death globally, generates severe damages to people’s immune systems and makes them susceptible to serious diseases. To date, there are no drugs that completely remove HIV from the body. This paper focuses on screening 224,205 natural compounds of ZINC15 NPs subset to identify those with bioactivity similar to non-nucleoside reverse transcriptase inhibitors (NNRTIs) as promising candidates to treat HIV-1. To reach the goal, an in silico approach involving 3D-similarity search, ADMETox, HIV protein-inhibitor prediction, docking, and MM-GBSA free-binding energies was trained. The FDA-approved HIV drugs, efavirenz, etravirine, rilpivirine, and doravirine, were used as queries. The prioritized compounds were subjected to ADMETox, docking, and MM-GBSA studies against HIV-1 reverse transcriptase (RT). Lys101, Tyr181, Tyr188, Trp229, and Tyr318 residues and free-binding energies have proved that ligands can stably bind to HIV-1 RT. Three natural products (ZINC37538901, ZINC38321654, and ZINC67912677) containing oxan and oxolan rings with hydroxyl substituents and one (ZINC2103242) having 3,6,7,8-tetrahydro-2H-pyrido[1 ,2-a]pyrazine-1,4-dione core exhibited comparable profiles to etravirine and doravirine, with ZINC2103242 being the most promising anti-HIV candidate in terms of drug metabolism and safety profile. These findings may open new avenues to guide the rational design of novel HIV-1 NNRTIs.

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Section: Resultsmentioning

confidence: 99%

Small Molecules of Natural Origin as Potential Anti-HIV Agents: A Computational Approach

Crisan

Bora

2021

Life

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“…Therefore, we decided to improve further the potency of these compounds by identifying structural analogs. Ligand 3D shape similarity is one of the commonly used virtual screening approaches to identify initial hits, − to identify structural analogs for potency improvement, to hop from one chemical scaffold to another − and to derive structure activity relationships for inhibitor optimization. , Compounds 2 and 11 were then used as queries to screen out compounds with significant 3D shape similarities from Namiki-Shoji compound collection. ROCS program was used for the evaluation of ligand 3D shape similarity and compounds were rank-ordered based on their TanimotoCombo score.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Fungal Denitrification Inhibitors by Targeting Copper Nitrite Reductase from Fusarium oxysporum

Matsuoka

Kumar²,

Muddassar³

et al. 2017

J. Chem. Inf. Model.

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The efficient application of nitrogenous fertilizers is urgently required, as their excessive and inefficient use is causing substantial economic loss and environmental pollution. A significant amount of applied nitrogen in agricultural soils is lost as nitrous oxide (NO) in the environment due to the microbial denitrification process. The widely distributed fungus Fusarium oxysporum is a major denitrifier in agricultural soils and its denitrification activity could be targeted to reduce nitrogen loss in the form of NO from agricultural soils. Here, we report the discovery of first small molecule inhibitors of copper nitrite reductase (NirK) from F. oxysporum, which is a key enzyme in the fungal denitrification process. The inhibitors were discovered by a hierarchical in silico screening approach consisting of pharmacophore modeling and molecular docking. In vitro evaluation of F. oxysporum NirK activity revealed several pyrimidone and triazinone based compounds with potency in the low micromolar range. Some of these compounds suppressed the fungal denitrification in vivo as well. The compounds reported here could be used as starting points for the development of nitrogenous fertilizer supplements and coatings as a means to prevent nitrogen loss by targeting fungal denitrification.

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“…In this context, cheminformatics approaches are systematically used in the early stages of drug development projects [11][12][13][14][15][16][17][18][19][20][21][22] and environmental science to assist the experiment in order to expedite and save resources and costs [23][24][25][26][27][28]. In silico tools can contribute significantly to exploring side effects by handling off-target interactions, which necessitates a thorough knowledge of structural information about off-target proteins [29][30][31][32][33]. Theoretical and experimental studies included in the review of Baweja GS et al [13] pointed out that minor structural changes could significantly or detrimentally influence the selectivity and inhibitory activity of various derivatives as potential MAO-B inhibitors.…”

Section: Introductionmentioning

confidence: 99%

New Insights on the Activity and Selectivity of MAO-B Inhibitors through In Silico Methods

Pacureanu

Bora

Crisan

2023

IJMS

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To facilitate the identification of novel MAO-B inhibitors, we elaborated a consolidated computational approach, including a pharmacophoric atom-based 3D quantitative structure–activity relationship (QSAR) model, activity cliffs, fingerprint, and molecular docking analysis on a dataset of 126 molecules. An AAHR.2 hypothesis with two hydrogen bond acceptors (A), one hydrophobic (H), and one aromatic ring (R) supplied a statistically significant 3D QSAR model reflected by the parameters: R2 = 0.900 (training set); Q2 = 0.774 and Pearson’s R = 0.884 (test set), stability s = 0.736. Hydrophobic and electron-withdrawing fields portrayed the relationships between structural characteristics and inhibitory activity. The quinolin-2-one scaffold has a key role in selectivity towards MAO-B with an AUC of 0.962, as retrieved by ECFP4 analysis. Two activity cliffs showing meaningful potency variation in the MAO-B chemical space were observed. The docking study revealed interactions with crucial residues TYR:435, TYR:326, CYS:172, and GLN:206 responsible for MAO-B activity. Molecular docking is in consensus with and complementary to pharmacophoric 3D QSAR, ECFP4, and MM-GBSA analysis. The computational scenario provided here will assist chemists in quickly designing and predicting new potent and selective candidates as MAO-B inhibitors for MAO-B-driven diseases. This approach can also be used to identify MAO-B inhibitors from other libraries or screen top molecules for other targets involved in suitable diseases.

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PLS and shape-based similarity analysis of maleimides – GSK-3 inhibitors

Cited by 11 publications

References 69 publications

Small Molecules of Natural Origin as Potential Anti-HIV Agents: A Computational Approach

Small Molecules of Natural Origin as Potential Anti-HIV Agents: A Computational Approach

Discovery of Fungal Denitrification Inhibitors by Targeting Copper Nitrite Reductase from Fusarium oxysporum

New Insights on the Activity and Selectivity of MAO-B Inhibitors through In Silico Methods

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