Discovery of potential epidermal growth factor receptor inhibitors from black pepper for the treatment of lung cancer: an in-silico approach.

A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is one of the main tumour markers in many cancer types and also plays a crucial role in cell proliferation, differentiation, angiogenesis, and apoptosis, which is a result of the auto-phosphorylations (kinase activity enhancement) that trigger signals involved in different cellular processes. Due to the discovery that non-small cell lung cancer (NSCLC) is a cause of this kinase activity enhancement, so far, several inhibitors have been tested against EGFR, but the side effects of these inhibitors necessitate an urgent measure to come up with an inhibitor that will be more specific to the cancer cells and not affect self-cells. This study was conducted to evaluate the efficacy of 37 compounds derived from Piper nigrum against EGFR using computer-aided drug design. Based on molecular docking, induced-fit docking, calculation of free binding energy, pharmacokinetics, QSAR prediction, and MD simulation. We propose five (5) lead compounds (clarkinol A, isodihydrofutoquinol B, Burchellin, kadsurin B, and lancifolin C) as a novel inhibitor, with clarkinol A demonstrating the highest binding affinity (-7.304 kcal/mol) with EGFR when compared with the standard drug (erlotinib). They also showed significant moderation for parameters investigated for a good pharmacokinetic profile, with a reliable R2 coefficient value predicted using QSAR models. The MD simulation of clarkinol A was found to be stable within the EGFR binding pocket throughout the 75 ns simulation run time. The findings showed that clarkinol A derived from Piper nigrum is worth further investigation and consideration as a possible EGFR inhibitor for the treatment of lung cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00197-1.

Identification of a 1, 8-naphthyridine-containing compound endowed with the inhibition of p53-MDM2/X interaction signaling: a computational perspective.

Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells. Consequently, this study explored the potential of a small molecule ligand containing 1, 8-naphthyridine scaffold to act as a dual inhibitor of p53-MDM2/X interactions using computational methods. The results obtained from quantum mechanical calculations revealed our studied compound entitled CPO is more stable but less reactive compared to standard dual inhibitor RO2443. Like RO2443, CPO also exhibited good non-linear optical properties. The results of molecular docking studies predicted that CPO has a higher potential to inhibit MDM2/MDMX than RO2443. Furthermore, CPO was stable over 50 ns molecular dynamics (MD) simulation in complex with MDM2 and MDMX respectively. On the whole, CPO also exhibited good drug-likeness and pharmacokinetics properties compared to RO2443 and was found with more anti-cancer activity than RO2443 in bioactivity prediction. CPO is anticipated to elevate effectiveness and alleviate drug resistance in cancer therapy. Ultimately, our results provide an insight into the mechanism that underlay the inhibition of p53-MDM2/X interactions by a molecule containing 1, 8-naphthyridine scaffold in its molecular structure.

Probing the bioactive compounds of Kigelia africana as novel inhibitors of TNF-α converting enzyme using HPLC/GCMS analysis, FTIR and molecular modelling.

Tumor Necrosis Factor Alpha Converting Enzyme (TACE) mediates inflammatory disorder and contributes to the pathophysiology of a variety of illnesses, such as chronic inflammation and cancer. This study identified metabolites in solvent extracts of Kigelia africana as putative TACE inhibitors due to the plant's known anti-inflammatory properties. HPLC-MS/GCMS analysis was used to characterize tentative phytochemicals from K. africana. The identified metabolites (n = 123) were docked with TACE to reveal the lead compounds. Binding free energy, ADMET prediction, molecular dynamics simulation at 100 ns, and DFT calculation were further conducted. The results revealed that K. africana contains sterol, phenols, alkaloids, terpenes and flavonoids. The FTIR shows that the extracts had peaks that correspond to the presence of different functional groups. The quantum polarized ligand docking (QPLD) analysis identified compound (n = 3) with binding affinity higher than standard compound IK-682. The hits also had modest ADMET profiles, interacted with essential residues within TACE binding pockets, and formed stable complexes with the protein. The 100 ns MD simulation shows that the compounds formed fairly stable interactions and complex with the protein as evidenced through RMSF, RMSD and MM-GBA results. The HOMO/LUMO, global descriptive molecular electrostatic potential Fukui function aid in the identification of the compounds' atomic sites prone to electrophilic/neutrophilic attacks, and non-covalent interactions. This study suggests that K. africana's bioactive compounds are capable of mitigating inflammation by inhibiting TACE.Communicated by Ramaswamy H. Sarma.

Virtual screening of natural compounds as selective inhibitors of polo-like kinase-1 at C-terminal polo box and N-terminal catalytic domain.

The over-expression of Polo-like kinase-1 (PLK1) is associated with cancer prognosis due to its pivotal role in cell proliferation. The N-terminal catalytic domain (NCD) and C-terminal polo box domain (PBD) of PLK1 are critical for the activity of the protein. Drugs that inhibit PLK1 by targeting these domains are on clinical trials, but so far, none has been approved by FDA. Thus, this study targets the two domains of PLK1 to identify compounds with inhibitory potential. Four validated e-pharmacophore models from NCD (PDB ID: 2OU7 and 4J52) and PBD (PDB ID: 5NEI and 5NN2) were used to screen over 26,000 natural compounds from NPASS database. Hits were identified after the well-fitted compounds were subjected to molecular docking study and ADME prediction. The pIC50 and electronic behaviour of the identified hits selectively targeting NCD and PBD of PLK1 were predicted via an externally validated QSAR model and quantum mechanics. The results showed that CAA180504, CAA197326, CAA74619, CAA328856 modulating PLK1 at NCD, and CBB130581, CBB230713, CBB206123, CBB12656 and CBB267117 modulating PLK1 at PBD had better molecular docking scores, pharmacokinetics and drug-like properties than NCD (volasertib) and PBD (purpurogallin) reference inhibitors. The compounds all had satisfactory inhibitory (pIC50) values which range from 6.187 to 7.157. The electronic behaviours of understudied compounds using HOMO/LUMO and global descriptive parameters revealed the atomic portion of the compounds prone to donating and accepting electrons. In conclusion, the hit compounds identified from the library of natural compounds are worthy of further experimental validation.Communicated by Ramaswamy H. Sarma.

Targeting p53-MDM2 interactions to identify small molecule inhibitors for cancer therapy: beyond "Failure to rescue".

At present, disrupting p53-MDM2 interactions through small molecule ligands is a promising approach to safe treatment and management of human cancer. Tumor cells unlike the normal cells, are rapidly evolving affecting the efficacy of many approved anti-cancer agents due to drug resistance. Therefore, identifying a potential anticancer compound is crucial. Pharmacophore based virtual screening, followed by molecular docking, ADMET evaluation, and molecular dynamics studies against MDM2 protein was investigated to identify potential ligands that may act as inhibitors. The model (AHRR_1) with survival score (4.176) was selected among the top ranked generated Pharmacophore hypothesis. Validation of the model hypothesis by an external dataset of actives and inactive compounds produced significant validation attributes including; AUC = 0.85, BEDROC = 0.56 at α = 20.0, RIE = 8.18, AUAC = 0.88, and EF of 6.2 at the top 2% of the dataset. The model was use for screening the ZINC database, and the top 1375 hits satisfying the model hypothesis were subjected to molecular docking studies to understand the molecular and structural basis of selectivity of compounds for MDM2 protein. A sub-set of 25 compounds with binding energy lower than the reference inhibitors were evaluated for pharmacokinetic properties. Four compounds (ZINC02639178, ZINC06752762, ZINC38933175, and ZINC77969611) showed the most desired pharmacokinetic profile. Lastly, investigation of the dynamic behaviour of leads-protein complexes through MD simulation showed similar RMSD, RMSF, and H-bond occupancy profile compared to a reference inhibitor, suggesting stability throughout the simulation time. However, ZINC02639178 was found to satisfy the molecular enumeration the most compared to the other three leads. It may emerge as potential treatment option after extensive experimental studies. Communicated by Ramaswamy H. Sarma.

Predictive hybrid paradigm for cytotoxic activity of 1,3,4-thiadiazole derivatives as CDK6 inhibitors against human (MCF-7) breast cancer cell line and its structural modifications: rational for novel cancer therapeutics.

The dysregulation of cyclin-CDK6 interactions has been implicated in human breast cancer, providing a rationale for more therapeutic options. Recently, ATP-competitive inhibitors have been employed for managing breast cancer. These molecules, like most natural CDKs inhibitors, potently bind in the ATP-binding site of CDK6 to regulate trans-activation. Nonetheless, only a few numbers of these molecules are approved to mitigate breast cancer, thus, ensuring that the search for more selective inhibitors continues. In this study, we attempted to establish the selective predictive models for identifying potent CDK6 inhibitors against a human breast cancer cell-line using a dataset of fifty-two 1,3,4-thiadiazole derivatives. The significant eight descriptor hybrid QSAR models generated exhibited encouraging statistical attributes including R2> 0.70, Q2LOO > 0.70, Q2LMO > 0.60, Qfn2 > 0.6. Furthermore, the study designed new compounds based on the activity and structural basis for selectivity of compounds for CDK6. While demonstrating good potency and modest selectivity, the compound C16, which showed significantly high activity of 5.5607 µM and binding energy value of -9.0 Kcal/mol, was used as template for compounds design to generate 10 novel series of 1,3,4-thiadiazole analogues containing benzisoselenazolone scaffolds, with significant pharmacological activity and better selectivity for CDK6. By our rationale, four of the designed compounds (C16b, C16h, C16i, and C16j) with activity values of 6.2584 µM, 6.7812 µM, 6.4717 µM, and 6.2666 µM respectively, and binding affinities of -10.0 kcal/mol, -9.9 kcal/mol, -9.9 kcal/mol, and -9.9 kcal/mol respectively, may emerge as therapeutic options for breast cancer treatment after extensive in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design.

Survivin is an apoptosis suppressing protein linked to different forms of cancer. As it stands, there are no approved drugs for the inhibition of survivin in cancer cells despite a number of promising compounds in clinical trials. This study designed a new set of compounds from fragments of active survivin inhibitors to potentiate their binding with survivin at BIR domain. Three hundred and five (305) fragments made from eight potent inhibitors of survivin were reconstructed to form a new set of compounds. The compounds were optimized using R group enumeration and bioisostere replacement after extensive docking analysis. The optimised compounds were filtered by a validated pharmacophore model to reveal how well they are aligned to the pharmacophore sites. Molecular docking of the well aligned compounds revealed the top-scoring compounds; and these compounds were compared with the eight inhibitors used as template for fragment-based design on the basis of binding affinity (rigid and flexible docking), predicted pIC50 and intermolecular interactions. The electronic behaviours (global descriptors, HOMO/LUMO, molecular electrostatic potential and Fukui functions) of newly designed compounds were calculated to investigate their reactivity and atomic sites prone to neutrophilic/electrophilic attack. The nine newly designed compounds had better rigid and flexible docking scores, free energy of binding and intermolecular interactions with survivin at BIR domain than the eight active inhibitors. Based on frontier molecular orbitals, OPE-3 was found to be the most reactive and less stable compound (0.13194 eV), followed by OPE-4 and OPE-9. The global descriptive parameters showed that OPE-3 had highest softness value (7.5245 eV) while OPE-8 recorded the maximum hardness value (0.08486 eV). The well-validated QSAR model also showed that OPE-3, OPE-7 and OPE-8 had the most significant bioactivity of all the inhibitors. This study thus provides new insight into the design of compounds capable of modulating the activity of survivin. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00108-8.

Induced Fit Docking and Automated QSAR Studies Reveal the ER-α Inhibitory Activity of Cannabis sativa in Breast Cancer.

BACKGROUND: Breast Cancer (BC), a common fatal disease and the deadliest cancer next to lung cancer, is characterized by an abnormal growth of cells in the tissues of the breast. BC chemotherapy is marked by targeting the activities of some receptors such as Estrogen Receptor alpha (ER-α). At present, one of the most commonly used and approved marketed therapeutic drugs for BC is tamoxifen. Despite the short-term success of tamoxifen usage, its long time treatment has been associated with significant side effects. Therefore, there is a pressing need for the development of novel anti-estrogens for the prevention and treatment of BC. OBJECTIVE: In this study, we evaluate the inhibitory effect of Cannabis sativa phytoconstituents on ER-α. METHODS: Glide and induced fit docking followed by ADME, automated QSAR and binding free energy (Δ>Gbind) studies were used to evaluate anti-breast cancer and ER-α inhibitory activity of Cannabis sativa, which has been reported to be effective in inhibiting breast cancer cell proliferation. RESULTS: Phyto-constituents of Cannabis sativa possess lower docking scores and good ΔGbind when compared to that of tamoxifen. ADME and AutoQSAR studies revealed that our lead compounds demonstrated the properties required to make them promising therapeutic agents. CONCLUSION: The results of this study suggest that naringenin, dihydroresveratrol, baicalein, apigenin and cannabitriol could have relatively better inhibitory activity than tamoxifen and could be a better and patent therapeutic candidate in the treatment of BC. Further research such as in vivo and/or in vitro assays could be conducted to verify the ability of these compounds.

Saponins in Cancer Treatment: Current Progress and Future Prospects.

Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.

Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2.

SARS-CoV-2 is a new strain of Coronavirus that caused the pneumonia outbreak in Wuhan, China and has spread to over 200 countries of the world. It has received worldwide attention due to its virulence and high rate of infection. So far, several drugs have experimented against SARS-CoV-2, but the failure of these drugs to specifically interact with the viral protease necessitates urgent measure to boost up researches for the development of effective therapeutics against SARS-CoV-2. Papain-like protease (PLpro) of the viral polyproteins is essential for maturation and infectivity of the virus, making it one of the prime targets explored for SARS-CoV-2 drug design. This study was conducted to evaluate the efficacy of ~ 50,000 natural compounds retrieved from IBS database against COVID-19 PLpro using computer-aided drug design. Based on molecular dock scores, molecular interaction with active catalytic residues and molecular dynamics (MD) simulations studies, STOCK1N-69160 [(S)-2-((R)-4-((R)-2-amino-3-methylbutanamido)-3-(4-chlorophenyl) butanamido) propanoic acid hydrochloride] has been proposed as a novel inhibitor against COVID-19 PLpro. It demonstrated favourable docking score, the free energy of binding, interacted with key amino acid residues necessary for PLpro inhibition and also showed significant moderation for parameters investigated for ADME/tox (Adsorption, distribution, metabolism, excretion and toxicological) properties. The edge of the compound was further established by its stability in MD simulation conducted for 30 ns employing GROMACS software. We propose that STOCK1N-69160 is worth further investigation for preventing SARS-CoV-2.

Insight into glycogen synthase kinase-3ß inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies.

Over activity of Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). This study aimed to find novel inhibitors of GSK-3ß from phyto-constituents of Melissa officinalis with the aid of computational analysis. Molecular docking, induced-fit docking (IFD), calculation of binding free energy via the MM-GBSA approach and Lipinski's rule of five (RO5) were employed to filter the compounds and determine their druggability. Most importantly, the compounds pIC50 were predicted by machine learning-based model generated by AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best model obtained was Model kpls_desc_38 (R2 = 0.8467 and Q2 = 0.8069), and this external validated model was utilized to predict the bioactivities of the lead compounds. While a number of characterized compounds from Melissa officinalis showed better docking score, binding free energy alongside adherence to RO5 than co-cystallized ligand, only three compounds (salvianolic acid C, ellagic acid and naringenin) showed more satisfactory pIC50. The results obtained in this study can be useful to design potent inhibitors of GSK-3ß.