Using filters in virtual screening: A comprehensive guide to minimize errors and maximize efficiency

Mahgoub, Radwa E.; Atatreh, Noor; Ghattas, Mohammad A.

doi:10.1016/bs.armc.2022.09.002

Cited by 11 publications

(14 citation statements)

References 103 publications

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“…The drug-likeness definition varies depending on the empirical rules employed within that concept, which has evolved with time. Developed in 1997, Lipinski’s rule of five (Ro5) was among the first set of quantitative parameters rules that defined the “drug-likeness” concept . The Ro5 considers a MW less than 500 g/mol, not more than five HBD, not more than ten HBA, and logP less than five .…”

Section: Results and Discussionmentioning

confidence: 99%

Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

Cedillo-González,

Medina-Franco

2023

ACS Omega

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G9a is a histone-lysine methyltransferase that performs the mono-and dimethylation of lysine 9 at histone 3 of the nucleosome. It belongs to the SET PKMT family, and its methylations are related to promoter repression and activation. G9a is a promising epigenetic target. Despite the fact that there are several G9a inhibitors under development, there are no compounds in clinical use due to adverse in vivo ADMET (absorption, distribution, metabolism, excretion, and toxicity) issues. The goal of this study is to discuss the exploration, characterization, and analysis of the chemical space of 409 G9a inhibitors reported in a large public database. Exploring the chemical space of the inhibitors led to the quantification of their structural diversity based on molecular scaffolds and structural fingerprints of different designs. As part of the analysis, the G9a inhibitors were compared with commercial libraries focused on epigenetic targets. The findings of this work will help in the development of, in a follow-up study, predictive models to identify G9a inhibitors. This study also points out the relevance of screening commercial libraries to expand the epigenetic relevant chemical space, in particular, G9a inhibitors.

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Section: Results and Discussionmentioning

confidence: 99%

Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

Cedillo-González,

Medina-Franco

2023

ACS Omega

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Section: Resultsmentioning

confidence: 99%

“…Hits obtained from screening may be promiscuous, exhibiting peculiar features such as an increased aggregation propensity, poor specificity and weak correlation between their structure and activity. [40] Hence, several assays were conducted to confirm the compounds' genuine inhibitory activity (Table S1). In the pre-incubation test, compounds EL01, BL15, CL12, and TL06 showed reduced inhibition after pre-incubation, suggesting non-specific inhibition.…”

Section: Promiscuity Tests Of Cl02 Cl12 Tl06 El01 and Bl15mentioning

confidence: 99%

The Discovery of Novel Small Oxindole‐Based Inhibitors Targeting the SARS‐CoV‐2 Main Protease (M^pro)

Alzyoud,

Mahgoub,

Mohamed

et al. 2023

Chemistry & Biodiversity

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With the potential for coronaviruses to re‐emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS‐CoV‐2 is essential. The Mpro enzyme is crucial for disease progression and the virus's life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug‐like molecules. Consequently, a commercially available ligand library containing ~7 million ligands was used to target site #2 via structure‐based virtual screening. After extensive filtering, docking, and post‐docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a Mpro non‐competitive reversible inhibitor with a Ki of 115 μM and an IC50 of 101.9 μM. Throughout the 200 ns‐long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, other oxindole derivatives were acquired for biological testing to gain deeper insights into their structure‐activity relationship. To sum up, drug‐like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic and other coronaviruses‐caused diseases.

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“…A compound that is too lipophilic may have poor solubility and bioavailability, while a compound that is too hydrophilic may have poor membrane permeability [ 59 ]. Lipophilicity exceeding five is often linked with undesired drug characteristics including limited water solubility, tissue accumulation, rapid metabolic turnover, and strong plasma protein binding [ 60 , 61 , 62 ]. Moreover, the literature indicates that compounds with moderate lipophilicity, oscillating around two, often show optimal abilities to reach molecular targets [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

Kibet,

Kimani,

Mwanza

et al. 2024

Pharmaceuticals

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Natural products hold immense potential for drug discovery, yet many remain unexplored in vast libraries and databases. In an attempt to fill this gap and meet the growing demand for effective drugs, this study delves into the promising world of ent-kaurane diterpenoids, a class of natural products with huge therapeutic potential. With a dataset of 570 ent-kaurane diterpenoids obtained from the literature, we conducted an in silico analysis, evaluating their physicochemical, pharmacokinetic, and toxicological properties with a focus on their therapeutic implications. Notably, these natural compounds exhibit drug-like properties, aligning closely with those of FDA-approved drugs, indicating a high potential for drug development. The ranges of the physicochemical parameters were as follows: molecular weights—288.47 to 626.82 g/mol; number of heavy atoms—21 to 44; the number of hydrogen bond donors and acceptors—0 to 8 and 1 to 11, respectively; the number of rotatable bonds—0 to 11; fraction Csp3—0.65 to 1; and TPSA—20.23 to 189.53 Å². Additionally, the majority of these molecules display favorable safety profiles, with only 0.70%, 1.40%, 0.70%, and 46.49% exhibiting mutagenic, tumorigenic, reproduction-enhancing, and irritant properties, respectively. Importantly, ent-kaurane diterpenoids exhibit promising biopharmaceutical properties. Their average lipophilicity is optimal for drug absorption, while over 99% are water-soluble, facilitating delivery. Further, 96.5% and 28.20% of these molecules exhibited intestinal and brain bioavailability, expanding their therapeutic reach. The predicted pharmacological activities of these compounds encompass a diverse range, including anticancer, immunosuppressant, chemoprotective, anti-hepatic, hepatoprotectant, anti-inflammation, antihyperthyroidism, and anti-hepatitis activities. This multi-targeted profile highlights ent-kaurane diterpenoids as highly promising candidates for further drug discovery endeavors.

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Using filters in virtual screening: A comprehensive guide to minimize errors and maximize efficiency

Cited by 11 publications

References 103 publications

Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

The Discovery of Novel Small Oxindole‐Based Inhibitors Targeting the SARS‐CoV‐2 Main Protease (M^pro)

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

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Using filters in virtual screening: A comprehensive guide to minimize errors and maximize efficiency

Cited by 11 publications

References 103 publications

Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

Diversity and Chemical Space Characterization of Inhibitors of the Epigenetic Target G9a: A Chemoinformatics Approach

The Discovery of Novel Small Oxindole‐Based Inhibitors Targeting the SARS‐CoV‐2 Main Protease (Mpro)

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

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Product

Resources

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The Discovery of Novel Small Oxindole‐Based Inhibitors Targeting the SARS‐CoV‐2 Main Protease (M^pro)