Discovery of new potential CDK2/VEGFR2 type II inhibitors by fragmentation and virtual screening of natural products

Vásquez, Andrés Felipe; Reyes, Alejandro; Duitama, Jorge; Barrios, Andrés

doi:10.1080/07391102.2020.1763839

Cited by 4 publications

(4 citation statements)

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“…While merging any NPDFs for each protein is certainly the next natural step to identify virtual candidates, we consider that this task is beyond the scope of this particular study and, therefore, it has not been included. However, the successful merging of one protein system reported here (CDK2/ VEGFR2) has been proved in a previous study focused on the design of dual inhibitors (Vásquez et al, 2020). In this previous study, a set of NPDFs, each one representing overlapping zones in both enzymes, was combined in drug-sized compounds able to occupy the active site of these highly challenging targets.…”

Section: Pharmacophore Models Were Able To Distinguish Between Active and Decoy Compoundsmentioning

confidence: 84%

“…These targets were arbitrarily selected from the DEKOIS 2.0 virtual library (http://www.dekois.com/) as a representative sample of 1) the main protein classes and 2) the "challenging" dataset levels established by (Bauer et al, 2013) (Table 1). One additional pair of models recently described by our research group for CDK2/ VEGFR2 was also included (Vásquez et al, 2020). We generated the models for each protein as overlapping pairs to promote an eventual development of NPDFs by a merging strategy (Hung et al, 2011;Scoffin and Slater, 2015) (Figure 3).…”

Section: Methodology Pharmacophore Models Generationmentioning

confidence: 99%

“…In this previous study, a set of NPDFs, each one representing overlapping zones in both enzymes, was combined in drug-sized compounds able to occupy the active site of these highly challenging targets. The entire merging strategy allowed counting on middle-sized fragments occupying more than one pocket in each enzyme (most probably using non-extensive fragments), which not only improved the chance of having a more similar positioning before and after the combining procedure but also proved appropriate for increasing chemical diversity in the section covering the overlapping region (interacting with a critical gatekeeper (GK) residue) (Vásquez et al, 2020).…”

Section: Pharmacophore Models Were Able To Distinguish Between Active and Decoy Compoundsmentioning

confidence: 99%

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Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

et al. 2021

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Fragment-based drug design (FBDD) and pharmacophore modeling have proven to be efficient tools to discover novel drugs. However, these approaches may become limited if the collection of fragments is highly repetitive, poorly diverse, or excessively simple. In this article, combining pharmacophore modeling and a non-classical type of fragmentation (herein called non-extensive) to screen a natural product (NP) library may provide fragments predicted as potent, diverse, and developable. Initially, we applied retrosynthetic combinatorial analysis procedure (RECAP) rules in two versions, extensive and non-extensive, in order to deconstruct a virtual library of NPs formed by the databases Traditional Chinese Medicine (TCM), AfroDb (African Medicinal Plants database), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products), and UEFS (Universidade Estadual de Feira de Santana). We then developed a virtual screening (VS) using two groups of natural-product-derived fragments (extensive and non-extensive NPDFs) and two overlapping pharmacophore models for each of 20 different proteins of therapeutic interest. Molecular weight, lipophilicity, and molecular complexity were estimated and compared for both types of NPDFs (and their original NPs) before and after the VS proceedings. As a result, we found that non-extensive NPDFs exhibited a much higher number of chemical entities compared to extensive NPDFs (45,355 vs. 11,525 compounds), accounting for the larger part of the hits recovered and being far less repetitive than extensive NPDFs. The structural diversity of both types of NPDFs and the NPs was shown to diminish slightly after VS procedures. Finally, and most interestingly, the pharmacophore fit score of the non-extensive NPDFs proved to be not only higher, on average, than extensive NPDFs (56% of cases) but also higher than their original NPs (69% of cases) when all of them were also recognized as hits after the VS. The findings obtained in this study indicated that the proposed cascade approach was useful to enhance the probability of identifying innovative chemical scaffolds, which deserve further development to become drug-sized candidate compounds. We consider that the knowledge about the deconstruction degree required to produce NPDFs of interest represents a good starting point for eventual synthesis, characterization, and biological activity studies.

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Section: Pharmacophore Models Were Able To Distinguish Between Active and Decoy Compoundsmentioning

confidence: 84%

Section: Methodology Pharmacophore Models Generationmentioning

confidence: 99%

Section: Pharmacophore Models Were Able To Distinguish Between Active and Decoy Compoundsmentioning

confidence: 99%

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Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

et al. 2021

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“…Carnosic acid docks to the binding site representative of type II kinase inhibitors. In general, type II inhibitors, such as sorafenib and lenvatinib, are often more specific than those targeting only the ATP binding site [ 107 , 108 ]. They represent a class of compounds that capture kinases in an inactive form and occupy both the adenine region (of ATP) as well as a hydrophobic pocket adjacent to the ATP binding site [ 109 ].…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insights into Biological Activities of Polyphenolic Compounds from Rosemary Obtained by Inverse Molecular Docking

Lešnik

Bren

2021

Foods

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Rosemary (Rosmarinus officinalis L.) represents a medicinal plant known for its various health-promoting properties. Its extracts and essential oils exhibit antioxidative, anti-inflammatory, anticarcinogenic, and antimicrobial activities. The main compounds responsible for these effects are the diterpenes carnosic acid, carnosol, and rosmanol, as well as the phenolic acid ester rosmarinic acid. However, surprisingly little is known about the molecular mechanisms responsible for the pharmacological activities of rosemary and its compounds. To discern these mechanisms, we performed a large-scale inverse molecular docking study to identify their potential protein targets. Listed compounds were separately docked into predicted binding sites of all non-redundant holo proteins from the Protein Data Bank and those with the top scores were further examined. We focused on proteins directly related to human health, including human and mammalian proteins as well as proteins from pathogenic bacteria, viruses, and parasites. The observed interactions of rosemary compounds indeed confirm the beforementioned activities, whereas we also identified their potential for anticoagulant and antiparasitic actions. The obtained results were carefully checked against the existing experimental findings from the scientific literature as well as further validated using both redocking procedures and retrospective metrics.

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Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review

Sabe

Ntombela

Jhamba

et al. 2021

European Journal of Medicinal Chemistry

373

178

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Discovery of new potential CDK2/VEGFR2 type II inhibitors by fragmentation and virtual screening of natural products

Cited by 4 publications

References 98 publications

Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

Mechanistic Insights into Biological Activities of Polyphenolic Compounds from Rosemary Obtained by Inverse Molecular Docking

Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review

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