Computational studies and synthesis of 131iodine-labeled nocardiotide A analogs as a peptide-based theragnostic radiopharmaceutical ligand for cancer targeting SSTR2.

Radiolabeled peptides belong to a highly specific group of radiotracers used in oncology, particularly for diagnostics and cancer therapy. With the notable advantages of high binding affinity and selectivity to cancer cells, they have proven to be very useful in nuclear medicine. As a result, efforts have been focused on discovering new peptide sequences for radiopeptide preparation. Nocardiotide A, a cyclic hexapeptide comprising the amino acids cyclo-Trp-Ile-Trp-Leu-Val-Ala (cWIWLVA) isolated from Nocardiopsis sp., has shown significant cytotoxicity against cancer cells, rendering it a suitable candidate for the process. Therefore, the present study aimed to design a stable and effective radiopeptide by labeling nocardiotide A with iodine-131 (131I), ensuring that its affinity to SSTR2 is not compromised. In silico study showed that structural modification of nocardiotide A labeled with 131iodine exhibited good affinity value, forming hydrogen bonds with key residues, such as Q.102 and T.194, which are essential in SSTR2. Based on the results, cyclic hexapeptides of cWIWLYA were selected for further synthesis, and its peptide product was confirmed by the presence of an ionic molecule peak m/z [M + Na]+ 855.4332 (yield, 25.60%). In vitro tests conducted on cWIWLYA showed that cWIWLYA can bind to HeLa cancer cells. Radiopeptide synthesis was initiated with radiolabeling of cWIWLYA by 131I using the chloramine-T method that showed a radiochemical yield of 93.37%. Non-radioactive iodine labeling reaction showed that iodination was successful, which detected the presence of di-iodinated peptide (I2-cWIWLYA) with m/z [M + Na]+ 1107.1138. In summary, a radiopeptide derived from nocardiotide A showed great potential for further development as a diagnostic and therapeutic agent in cancer treatment.

Alpha-mangostin, piperine and beta-sitosterol as hepatitis C antivirus (HCV): In silico and in vitro studies.

Hepatitis C is still a serious liver case of health. Up to now the development of anti-Hepatitis C Virus (HCV) drugs is challenging, especially the development of natural material compounds as anti-HCV. In the present study, we evaluated the probability of α-mangostin, piperine, and ß-sitosterol as anti-HCV with the in silico and in vitro approaches. Molecular docking was performed between nonstructural protein 5B (NS5B, PDB ID 3FQL) with α-mangostin, piperine, and ß-sitosterol by Autodock Tools® and BIOVIA Discovery Studio®. Subsequently, molecular dynamics simulations were conducted for 200 ns, evaluating the dynamic interaction between the ligands and the viral protein NS5B. Furthermore, compound characterization at the hepatocarcinoma cell line was employed. α-Mangostin with NS5B complex demonstrated the most negative binding free energy value based on MM-PBSA calculation with a value of -9.13 kcal/mol. In vitro test showed that IC50 of α -mangostin was 2.70 ± 0.92 µM, IC50 of piperine was 52.18 ± 3.21 µM, IC50 of ß-sitosterol was >100 µM. α-Mangostin can serve as a valuable lead compound for further development of the anti-HCV.

In Vivo Pharmacodynamics of Calophyllum soulattri as Antiobesity with In Silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies.

This study aims to determine the antiobesity activity of Calophyllum soulattri leaves extract (CSLE) on high fat diet-fed rats (HFD) and to predict the molecular docking and pharmacokinetics of selected compounds of Calophyllum soulattri to fat mass and obesity-associated protein (FTO). Daily body weight, organ, carcass fat (renal and anal), body mass index, total cholesterol, and total triglyceride levels were observed after CSLE was given orally for 50 days. Furthermore, body mass index of a CSLE dose of 50 mg/kgbw, 100 mg/kgbw and orlistat (120 mg/kgbw) group are 0.68, 0.57 and 0.52, respectively. The total body weight of the CLSE dose of 100 mg/kgbw group showed the lowest percentage change, followed by a CLSE dose of 50 mg/kgbw compared to the normal and positive control group. The carcass fat index of CSLE dose of 100 mg/kgbw was not significantly different from orlistat, which was in line with its total cholesterol level and triglyceride (p < 0.05). The binding affinity of selected compounds from Calophyllum soulattri (friedelin, caloxanthone B, macluraxanthone, stigmasterol, trapezifolixanthone, dombakinaxanthone, and brasixanthone B) to FTO are -8.27, -9.74, -8.48, -9.34, -8.85, -8.68 and -9.39 kcal/mol, which are better than that of orlistat at -4.80 kcal/mol. The molecular dynamics simulation showed that the interaction between Caloxanthone B compounds and obesity receptors was relatively stable. Lipinski's rule determined the absorption percentage of all compounds above 90% with good drug-likeness. The results showed the potential of CSLE as an antiobesity drug candidate.

Computational Prediction of Resistance Induced Alanine-Mutation in ATP Site of Epidermal Growth Factor Receptor.

Epidermal growth factor receptor (EGFR) resistance to tyrosine kinase inhibitors can cause low survival rates in mutation-positive non-small cell lung cancer patients. It is necessary to predict new mutations in the development of more potent EGFR inhibitors since classical and rare mutations observed were known to affect the effectiveness of the therapy. Therefore, this research aimed to perform alanine mutagenesis scanning on ATP binding site residues without COSMIC data, followed by molecular dynamic simulations to determine their molecular interactions with ATP and erlotinib compared to wild-type complexes. Based on the result, eight mutations were found to cause changes in the binding energy of the ATP analogue to become more negative. These included G779A, Q791A, L792A, R841A, N842A, V843A, I853A, and D855A, which were predicted to enhance the affinity of ATP and reduce the binding ability of inhibitors with the same interaction site. Erlotinib showed more positive energy among G779A, Q791A, I853A, and D855A, due to their weaker binding energy than ATP. These four mutations could be anticipated in the development of the next inhibitor to overcome the incidence of resistance in lung cancer patients.

Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors.

Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug's ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.

A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations.

The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.

Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment.

In cell development, the cell cycle is crucial, and the cycle progression's main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy's effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.

Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBß.

Nuclear receptor REV-ERBß is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBß to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBß. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBß in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBß binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBß were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBß was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBß, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBß to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.

Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for binding with VEGFR2. However, the existence of VEGF up-regulation independent of EGFR leads to cancer cell resistance to anti-EGFR. Therefore, a therapeutic approach targeting EGFR and VEGFR2 simultaneously may improve the outcome of cancer treatment. The present study was designed to identify potential compounds as a dual inhibitor of EGFR and VEGFR2 by the computational method. Firstly, the ligand-based pharmacophore model for each target was setup to screen of ZINC database of purchasable compounds. The hit compounds obtained by pharmacophore screening were then further screened by molecular docking studies. Taking erlotinib (EGFR inhibitor) and axitinib (VEGFR2 inhibitor) as reference drugs, six potential compounds (ZINC08398597, ZINC12047553, ZINC16525481, ZINC17418102, ZINC21942954, and ZINC38484632) were selected based on their docking scores and binding interaction. However, molecular dynamics simulations demonstrated that only ZINC16525481 and ZINC38484632 which have good binding free energy and stable hydrogen bonding interactions with EGFR and VEGFR2. The result represents a promising starting point for developing potent dual tyrosine kinases inhibitor of EGFR and VEGFR2.

In Silico Study, Synthesis, and Cytotoxic Activities of Porphyrin Derivatives.

Five known porphyrins, 5,10,15,20-tetrakis(p-tolyl)porphyrin (TTP), 5,10,15,20-tetrakis(p-bromophenyl)porphyrin (TBrPP), 5,10,15,20-tetrakis(p-aminophenyl)porphyrin (TAPP), 5,10,15-tris(tolyl)-20-mono(p-nitrophenyl)porphyrin (TrTMNP), 5,10,15-tris(tolyl)-20-mono(p-aminophenyl)porphyrin (TrTMAP), and three novel porphyrin derivatives, 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di(p-tolyl)porphyrin (DBECPDTP), 5,10-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-15,20-di-(methylpyrazole-4-yl)porphyrin (cDBECPDPzP), 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di-(methylpyrazole-4-yl)porphyrin (DBECPDPzP), were used to study their interaction with protein targets (in silico study), and were synthesized. Their cytotoxic activities against cancer cell lines were tested using 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay. The interaction of porphyrin derivatives with carbonic anhydrase IX (CAIX) and REV-ERBß proteins were studied by molecular docking and molecular dynamic simulation. In silico study results reveal that DBECPDPzP and TrTMNP showed the highest binding interaction with REV- ERBß and CAIX, respectively, and both complexes of DBECPDPzP-REV-ERBß and TrTMNP-CAIX showed good and comparable stability during molecular dynamic simulation. The studied porphyrins have selective growth inhibition activities against tested cancer cells and are categorized as marginally active compounds based on their IC50.

In silico study of porphyrin-anthraquinone hybrids as CDK2 inhibitor.

Cyclin-Dependent Kinases (CDKs) are known to play crucial roles in controlling cell cycle progression of eukaryotic cell and inhibition of their activity has long been considered as potential strategy in anti-cancer drug research. In the present work, a series of porphyrin-anthraquinone hybrids bearing meso-substituents, i.e. either pyridine or pyrazole rings were designed and computationally evaluated for their Cyclin Dependent Kinase-2 (CDK2) inhibitory activity using molecular docking, molecular dynamics simulation, and binding free energy calculation. The molecular docking simulation revealed that all six porphyrin hybrids were able to bind to ATP-binding site of CDK2 and interacted with key residues constituted the active cavity of CDK2, while molecular dynamics simulation indicated that all porphyrins bound to CDK2 were stable for 6ns. The binding free energies predicted by MM-PBSA method showed that most compounds exhibited higher affinity than that of native ligand (4-anilinoquinazoline, DTQ) and the affinity of mono-H2PyP-AQ was about three times better than that of DTQ, indicating its potential to be advanced as a new CDK2 inhibitor.