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Compounds from Natural Sources As Protein Kinase Inhibitors

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Compounds from Natural Sources As Protein Kinase Inhibitors biomolecules Review Compounds from Natural Sources as Protein Kinase Inhibitors Andrea Baier 1,* and Ryszard Szyszka 2 1 Department of Animal Physiology and Toxicology, Institute of Biological Sciences, The John Paul II Catholic University of Lublin, 20-950 Lublin, Poland 2 Department of Molecular Biology, Institute of Biological Sciences, The John Paul II Catholic University of Lublin, 20-950 Lublin, Poland; [email protected] * Correspondence: [email protected] Received: 30 September 2020; Accepted: 9 November 2020; Published: 12 November 2020 Abstract: The advantage of natural compounds is their lower number of side-effects when compared to most synthetic substances. Therefore, over the past several decades, the interest in naturally occurring compounds is increasing in the search for new potent drugs. Natural compounds are playing an important role as a starting point when developing new selective compounds against different diseases. Protein kinases play a huge role in several diseases, like cancers, neurodegenerative diseases, microbial infections, or inflammations. In this review, we give a comprehensive view of natural compounds, which are/were the parent compounds in the development of more potent substances using computational analysis and SAR studies. Keywords: protein kinases; inhibitors; natural compounds 1. Protein Kinases as Therapeutic Targets Protein phosphorylation is one of the most frequent and significant post-translational modifications [1,2]. Protein kinases, which are nearly all members of the eukaryotic protein kinase (ePK) superfamily, represent a large and diverse family of enzymes. They catalyze covalent modification of proteins by attaching phosphate groups (from ATP or GTP) mainly to serine, threonine, and/or tyrosine residues. Phosphorylation has many effects on proteins. The added charge and bulk of the phosphate group modifies the protein from hydrophobic apolar to hydrophobic polar. This may result in changes in protein conformation and/or alter the enzyme activity and, therefore, influence the interaction between proteins, localization, or the degradation of protein substrates. Protein kinases catalyzing the process of phosphorylation are base elements of cell signaling transduction cascades, such as the control of cell growth and proliferation, response to extracellular stimuli, DNA damage response, control of metabolism, and death. Reversible protein phosphorylation is the main strategy for the control of eukaryotic cell activities. Figure1 presents an overview of signaling pathways, the protein kinases involved, and the potential targets of natural substances. Biomolecules 2020, 10, 1546; doi:10.3390/biom10111546 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1546 2 of 30 Biomolecules 2020, 10, x FOR PEER REVIEW 2 of 31 FigureFigure 1. Schematic 1. Schematic presentation presentation of intracellularof intracellular transduction transduction pathways, pathways, including including proteinprotein kinases and and examples of their inhibition by natural compounds. examples of their inhibition by natural compounds. The first complete study of human kinases identified and classified 518 protein kinases by The first complete study of human kinases identified and classified 518 protein kinases by grouping them into evolutionary related families based on statistical sequence analysis and biological groupingfunction them [3–5]. into In evolutionary addition, this related analysis families showed based that 478 on of statistical them possessed sequence catalytic analysis domains andbiological with functionrelated [3– 5primary]. In addition, sequences. this Thirty-two analysis showed atypical thatkinases 478 (e.g., of them PI3K, possessed RIO kinase) catalytic with domainsdissenting with relatedprimary primary sequences sequences. have Thirty-two been identified atypical [3]. kinasesIn a later (e.g., study, PI3K, two RIO novel kinase) kinases with were dissenting added that primary sequencescontained have an been interesting identified combination [3]. In a later of study,kinase two and novel acyl-CoA kinases dehydrogenase were added thatdomains contained [6]. an interestingSubsequent combination analysis of the kinase human and kinome acyl-CoA led to dehydrogenase the identification domains of 23 new [6]. kinases Subsequent and removed analysis of the humanthree for kinome a total of led 538 to protein the identification kinases [6–8].of A 23recent new reassessment kinases and of removedthe human threekinase for superfamily a total of 538 proteinshowed kinases 555 [ 6members–8]. A recent grouped reassessment into main classes of the humanof 497 eukaryotic kinase superfamily protein kinases showed (ePKs) 555 and members 58 groupedatypical into protein main classeskinases (aPKs), of 497 eukaryoticdue to lack of protein sequence kinases similarity (ePKs) [9]. This and shows 58 atypical that gene protein encoding kinases for protein kinases make up almost 2% of the human genome and control essential biological (aPKs), due to lack of sequence similarity [9]. This shows that gene encoding for protein kinases make processes. up almostThe 2% of555 the humanhuman genomeprotein andkinases control (KinBase essential: biologicalwww.kinase.com/web/current/kinbase/) processes. Thephosphorylate 555 human either protein serine/threonine kinases (KinBase: (Ser-/Thr-sp www.kinase.comecific protein/web kinases;/current S/T/ kinbasePKs), tyrosine/) phosphorylate (Tyr- eitherspecific serine/ threonineprotein kinases; (Ser-/ Thr-specificT PKs), or both protein Ser/Thr kinases; as well S as/T Tyr PKs), (dual-specificity tyrosine (Tyr-specific protein kinases) protein kinases;[1– T PKs),4]. orA bothtotal of Ser 497/Thr protein as well kinases as Tyr have (dual-specificity a common catalytic protein site, kinases) which contains [1–4]. A a totalglycine-rich of 497 proteinN- kinasesterminal have aATP-binding common catalytic pocket and site, a which conserved contains central a glycine-richaspartic acid N-terminalresidue required ATP-binding for catalytic pocket and aactivity conserved [4,5]. centralThe ePK asparticclass is further acid residuesubdivided required on the forbasis catalytic of primary activity sequences [4,5 ].into The nine ePK major class is furthergroups, subdivided and each on group the basis is then of primarysplit into sequencesfamilies [3,4]. into In nineTable major 1, a number groups, of and eukaryotic each group protein is then split intokinases families are listed, [3,4]. and In Tabletheir bi1,ological a number functions of eukaryotic are given. protein kinases are listed, and their biological functions are given. Table 1. Selected ePKs and their cellular functions. ePK Function in the Cell Ref. − Glucose storage regulation in the form of glycogen by phosphorylation of GSK3. − Regulation of cell survival via phosphorylation of ASK1. Akt/PKB [10,11] − Regulation of many processes, including metabolism, proliferation, cell survival, growth, and angiogenesis. Biomolecules 2020, 10, 1546 3 of 30 Table 1. Selected ePKs and their cellular functions. ePK Function in the Cell Ref. - Glucose storage regulation in the form of glycogen by phosphorylation of GSK3. - Regulation of cell survival via phosphorylation of ASK1. Akt/PKB - Regulation of many processes, including metabolism, proliferation, cell survival, [10,11] growth, and angiogenesis. - Control of food intake. - Key role in carbohydrate and lipid metabolism in skeletal muscle. AMPK - Promotion of catabolic pathways to generate ATP production and inhibition of [12,13] anabolic pathways. - Negative regulation of mTOR signaling. - Positive regulation of vascular smooth muscle proliferation. - Crucial role in the apoptosis signal transduction pathway through ASK1 mitochondria-dependent caspase activation required for sustained activations of [14] JNK/p38 MAP kinases and apoptosis. - Regulation of cell cycle and cell division. CDKs - Modulation of transcription in response to several extra- and intracellular cues. [15–17] - Positive regulation of cell growth and proliferation. - Stimulation of Wnt signaling pathway. CK2, CK2α - Regulation of signal transduction by p53 mediator. [18–20] - Repression of cysteine-type endopeptidases involved in apoptosis. - Negative regulation of ubiquitin-dependent protein degradation. - Regulation of angiogenesis, cell motility, differentiation, proliferation, and survival. - Inhibition of apoptosis. EGFR - Positive regulation of NFκB signaling. [21–24] - Activation of major downstream signaling cascades, including the RAS-RAF-MEK-ERK, PI3K-Akt, PLCγ-PKC, and STATs modules. - Positive regulation of gene expression and translation. ERK1/2 - Regulation of proliferation, differentiation, and survival. [25,26] - Regulation of apoptosis and stress response. - Positive regulation of PI3K and Akt/PKB signaling. FAK1 - Positive regulation of cell population proliferation and cell migration. [27,28] - Regulation of cell adhesion mediated by integrin. - Cell proliferation, differentiation, maturation, and migration. FGFR - Selective apoptosis during embriogenesis. [29–31] - Stimulation of MAPK, PI3K, and Akt/PKB signaling pathways. - A negative regulator in the hormonal control of glucose homeostasis, Wnt signaling, and the regulation of transcription factors and microtubules by inactivation of GSK3β glycogen synthase, eIF2B, β-catenin, APC, JUN, and others. [32] - Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. - Regulation of cell growth and survival, suppression of apoptosis. - Inactivation of MAPKK
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