Virtual screening and molecular dynamics simulation of natural compounds as potential inhibitors of serine/threonine kinase 16 for anticancer drug discovery.

Serine/threonine kinase 16 (STK 16) is involved in many facets of cellular regulation; activation of STK 16 plays a crucial role in the migration of cancer cells. Therefore, it is a novel target for the discovery of anticancer agents. Herein, virtual screening and dynamics simulation were used to screen a large library of natural compounds against STK 16 using Schrodinger suit 2021-2 and GROMACS 2021.6. The results predicted five molecules with high binding affinity against the target, with NPC132329 (Arcyriaflavin C) and NPC160898 having higher binding affinity and molecular mechanics generalized born surface area (MM/GBSA), suggesting that it is better than the standard inhibitor. The molecular dymanics (MD) simulation studies showed that the STK 16-NPC132329 complex has the lowest root mean square deviation, and STK 16-NPC160898 was the most stable compared with the standard drug and selective STK 16 inhibitor. The minimal fluctuation was observed in the STK 16-NPC132329 and STK 16-NPC160898 complexes based on the root mean square fluctuation trajectory with NPC132329 and NPC160898 forming 2 and 3 hydrogen bonds respectively with the amino acid residue of the target's binding site. Overall, NPC132329 and NPC160898 are better STK 16 inhibitors than the standard drug and selective inhibitor, which can be further studied to discover novel anticancer drugs.

Integrating biocomputational techniques for Breast cancer drug discovery via the HER-2, BCRA, VEGF and ER protein targets.

Computational modelling remains an indispensable technique in drug discovery. With myriad of high computing resources, and improved modelling algorithms, there has been a high-speed in the drug development cycle with promising success rate compared to the traditional route. For example, lapatinib; a well-known anticancer drug with clinical applications was discovered with computational drug design techniques. Similarly, molecular modelling has been applied to various disease areas ranging from cancer to neurodegenerative diseases. The techniques ranges from high-throughput virtual screening, molecular mechanics with generalized Born and surface area solvation (MM/GBSA) to molecular dynamics simulation. This review focuses on the application of computational modelling tools in the identification of drug candidates for Breast cancer. First, we begin with a succinct overview of molecular modelling in the drug discovery process. Next, we take note of special efforts on the developments and applications of combining these techniques with particular emphasis on possible breast cancer therapeutic targets such as estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF), breast cancer gene 1 (BRCA1), and breast cancer gene 2 (BRCA2). Finally, we discussed the search for covalent inhibitors against these receptors using computational techniques, advances, pitfalls, possible solutions, and future perspectives.

Design of small molecules for CDK-2 inhibition in colorectal cancer based on substructure search.

The global frequency of colorectal cancer motivates extensive drug discovery efforts. CDK2, a key member of the CDK family, has been linked to tumor progression, unregulated cell proliferation, and growth promotion. Water-soluble flavonoids with a fast metabolism called anthocyanins have been shown to have a variety of pharmacological properties, including anti-cancer properties. This study aims to find possible CDK2 inhibitors from Anthocyanin-like molecules. Anthocyanins sourced from PubChem were screened using a virtual screening approach that included a KNIME workflow, QSAR-model, Pharmacophore hypothesis, and a structure-based screening to identify compounds with a better binding affinity and predicted bioactivity compared to the standard, Sorafenib. The top compounds were subjected to a 100 ns MD simulation to confirm their stability at the active site. Compounds 1-5 were shown to have higher binding affinity and bioactivity in this study. These substances interacted with the critical amino acids (LEU 83, ASP 145 and LYS 89) at CDK2's active site. Compared to the reference with a pIC50 value of 6.003 nM, the top compounds listed have superior predicted bioactivity ranging from 6.539 to 6.36 nM. Also, ADMET predictions predicted that Compounds 1-5 were not carcinogenic and not a p-glycoprotein substrate. MD simulation also validated Compound 1's stability at the active site compared to the standard. This study uncovers potential CDK2 inhibitors with good binding affinities, shedding light on their interactions with the target protein. While promising, further in vivo and in vitro investigations are essential to validate the anticancer potential of these compounds.Communicated by Ramaswamy H. Sarma.

Unveiling the Chemical Profiling Antioxidant and Anti-Inflammatory Activities of Algerian Myrtus communis L. Essential Oils, and Exploring Molecular Docking to Predict the Inhibitory Compounds against Cyclooxygenase-2.

Considering the large spectrum of side effects caused by synthetic drugs and the development of natural alternatives utilizing Algerian flora, this study aimed to place a spotlight on the chemical profile and antioxidant and anti-inflammatory activities of Myrtus communis L. essential oils (MCEOs). In this study, essential oils (EOs) were collected via hydro-distillation of the plant's leaves, and a chemical constituent analysis was performed using gas chromatography-mass spectrophotometry (GC-MS). The in vitro antioxidant activity was evaluated using DPPH, ABTS, and hydroxyl radical scavenging tests. The in vitro anti-inflammatory capacity was estimated by studying the antidenaturation effect using bovine serum albumin (BSA) as a protein model. The in vivo anti-inflammatory activity was carried out by utilizing the classical model of carrageenan-induced paw edema in rats, using diclofenac (DCF) as the reference drug. Moreover, the molecular interaction of the compounds obtained from the GC-MS analysis was studied within the binding site of cyclooxygenase-2 (COX-2) using an in silico approach as the confirmatory tool of the in vitro and in vivo experiments. The GC-MS analysis revealed that MCEOs were mainly composed of oxygenated monoterpenes (70.56%), oxygenated sesquiterpenes (3.1%), sesquiterpenes (4.17%), and monoterpenes (8.75%). Furthermore, 1,8-cineole was the major compound (19.05%), followed by cis-geranyl acetate (11.74%), methyl eugenol (5.58%), α-terpineol (4.62%), and ß-myrcene (4.40%). MCEOs exhibited remarkable concentration-dependent free radical scavenging activity, with an IC50 of 15.317 ± 0.340 µg/mL, 18.890 ± 2.190 µg/mL, and 31.877 ± 0.742 µg/mL for DPPH, ABTS, and hydroxyl radical, respectively. The significant in vitro anti-inflammatory activity due to the inhibition of BSA denaturation was proportional to the EO concentration, where the highest value was recorded at 100 µg/mL with an approximately 63.35% percentage inhibition and an IC50 of 60.351 ± 5.832 µg/mL. MCEOs showed a good in vivo anti-inflammatory effect by limiting the development of carrageenan-induced paw thickness. The in silico study indicated that, among the 60 compounds identified by the GC-MS analysis, 9 compounds were observed to have a high binding energy to cyclooxygenase-2 as compared to diclofenac. Our study revealed that EOs from Algerian Myrtus communis L. can be considered to be a promising candidate for alleviating many debilitating health problems and may provide new insights in the fields of drug design, agriculture, and the food industry.

Computational prediction of 11ß-hydroxysteroid dehydrogenase inhibitors from n-butanol fraction of Blighia welwetschii (Hiern) leaf for the management of type-2 diabetes.

Human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) is an enzyme that catalyzes the generation of active cortisol from cortisone, thus regulating the availability of glucocorticoids for the steroid receptor. The involvement of this process in insulin insensitivity has established the catalyst as therapeutic target in type-2 diabetes management. Herein, potent antagonists of 11ß-HSD-1 were predicted from bioactive compounds identified from n-butanol fraction of B. welwitschi leaf using chromatography method (HPLC). Molecular docking, MM/GBSA evaluation, autoQSAR modeling, e-pharmacophore modeling, and molecular dynamics simulation of the bioactive compounds were carried out against 11ß-HSD-1 employing Schrodinger suite (2017-1). Seven out of the ten bioactive compounds from the fraction showed a higher degree of binding affinity against 11ß-HSD-1 compared with the co-crystalized ligand. The post-docking analysis revealed strong interaction due to the hydrogen bond formation between the molecules and amino acid present at the catalytic site of 11ß-HSD-1. Rutin showed the highest binding affinity (-13.980 kcal/mol) among the hits comparable to the co-crystalized ligand (-7.576 kcal/mol). The binding free energy (ΔGbind) evaluation validates the inhibitory potential of the docked complexes, which exclusively confirmed cyaniding-3-o-glucoside (-62.022 kcal/mol) with the highest binding energy followed by rutin (-59.629 kcal/mol). The molecular dynamics simulations predicted the stability of rutin and quercetin-3-o-glycoside complex with 11ß-HSD-1 through 100 ns with minimum fluctuation and more H-bond observed between the two top scored 11ß-HSD-1-compound complexes compared to the 11ß-HSD-1-co-crystalized ligand complex. The pharmacokinetic profile revealed that the hit compounds are promising drug candidates except for rutin which violated more than one Lipinski's rule of five. This study revealed that bioactive compounds identified from B. welwitschi leaves demonstrated good inhibitory potential against 11ß-HSD-1. Therefore, these bioactive molecules require experimental validation as 11ß-HSD-1 antagonists for type 2 diabetes management.Communicated by Ramaswamy H. Sarma.

Vitellaria paradoxa inhibits arsenic-induced toxicity in Drosophila melanogaster via the augmentation of antioxidant system.

The Ethyl Acetate Fraction (EACF) of Ethanol Leaf Extract of Vitellaria paradoxa (ELVp) was assessed against Sodium Arsenite (SA)-induced toxicity in Drosophila melanogaster. The Gas Chromatography-Mass Spectrometry (GC-MS) analysis of EACF was carried out. The molecular docking of the compounds obtained from GC-MS was performed against D. melanogaster glutathione-S-transferase-2 (GST-2). Firstly, D. melanogaster (Harwich strain) was treated with EACF to determine its effect on longevity. Secondly, D. melanogaster was fed with EACF (1.0 and 3.0 mg/5 g diet) and/or SA (0.0625 mM) for 5 days. Thereafter, the ameliorative role of EACF in SA-induced toxicity was evaluated using the fly's emergence rate, locomotor activity, oxidative stress and antioxidant biomarkers. The in-silico study revealed varying degrees of binding affinity of the twelve active compounds of EACF against GST-2 which was comparable with the co-crystalized ligand (glutathione). The EACF increased the longevity of D. melanogaster by 20.0 % compared with control and ameliorated SA-induced reduction of emergence rate and locomotor performance by 178.2 and 20.5 %, respectively. Additionally, EACF ameliorated SA-induced reduction of total thiol and non-protein thiols and inhibition of catalase and GST activities (p < 0.05). These results corroborated with histological data obtained in the fat body of D. melanogaster. Overall, EACF augmented the antioxidant system of D. melanogaster and prevented sodium arsenite-induced oxidative stress due to its high antioxidant property.

QSAR-based virtual screening of traditional Chinese medicine for the identification of mitotic kinesin Eg5 inhibitors.

Cell division is a crucial process for the growth and development of all living organisms. Unfortunately, uncontrolled cell division and growth is a hallmark of cancer, leading to the formation of tumors. The Human Eg5 protein, also known as the mitotic kinesin Eg5, plays a vital role in the regulation of cell division and its dysfunction has been linked to cancer development. This study aimed to identify new inhibitors of the Human Eg5 protein. Over 2000 Traditional Chinese Medicine (TCM) compounds were screened through a combination of virtual and structure-based screening methods. The top five compounds (Compounds 1-5) showed improved binding affinity to Human Eg5 compared to the standard drug Monastrol, as demonstrated by docking and MMGBSA scores, as well as interactions with key amino acids GLY 116 and GLY 118. The potential absorption and bioactivity of these compounds were also predicted through ADMET properties and a QSAR model, respectively, and showed improved results compared to the standard. Further quantum mechanics docking confirmed the better binding affinity of the lead compound, Compound 1. Our findings highlight Compound 1-5 as promising hits for inhibiting Human Eg5 and the need for experimental validation of their potential in treating cancer.

Antidiabetes study of Spondias mombin (Linn) stem bark fractions in high-sucrose diet-induced diabetes in Drosophila melanogaster.

Objective: The onset of insulin resistant diabetes has been associated with a high-sucrose diet in vertebrates and invertebrates. However, various parts of Spondias mombin reportedly possess antidiabetic potential. However, the antidiabetic efficacy of S. mombin stem bark in high-sucrose diet-induced Drosophila melanogaster model has not been explored. In this study, the antidiabetic and antioxidant effects of the solvent fractions of S. mombin stem bark were evaluated using in vitro, in vivo, and in silico methods. Methods: Successive fractionation of S. mombin stem bark ethanol extract was performed; the resulting fractions were subjected to in vitro antioxidant and antidiabetic assays using standard protocols. The active compounds identified from the high-performance liquid chromatography (HPLC) study of the n-butanol fraction were docked against the active site of Drosophila α-amylase using AutoDoc Vina. The n-butanol and ethyl acetate fractions of the plant were incorporated into the diet of diabetic and nondiabetic flies to study the in vivo antidiabetic and antioxidant properties. Results: The results obtained revealed that n-butanol and ethyl acetate fractions had the highest in vitro anti-oxidant capacity by inhibiting 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power, and hydroxyl radical followed by significant inhibition of α-amylase. HPLC analysis revealed the identification of eight compounds with quercetin having the highest peak followed by rutin, rhamnetin, chlorogenic acid, zeinoxanthin, lutin, isoquercetin, and rutinose showing the lowest peak. The fractions restored the glucose and antioxidant imbalance in diabetic flies, which is comparable with the standard drug (metformin). The fractions were also able to upregulate the mRNA expression of insulin-like peptide 2, insulin receptor, and ecdysone-inducible gene 2 in diabetic flies. The in silico studies revealed the inhibitory potential of active compounds against α-amylase with isoquercetin, rhamnetin, rutin, quercetin, and chlorogenic acid having higher binding affinity than the standard drug (acarbose). Conclusion: Overall, the butanol and ethyl acetate fractions of S. mombin stem bark ameliorate type 2 diabetes in Drosophila. However, further studies are needed in other animal models to confirm the antidiabetes effect of the plant.

Protein-protein interaction and interference of carcinogenesis by supramolecular modifications.

Protein-protein interactions (PPIs) are essential in normal biological processes, but they can become disrupted or imbalanced in cancer. Various technological advancements have led to an increase in the number of PPI inhibitors, which target hubs in cancer cell's protein networks. However, it remains difficult to develop PPI inhibitors with desired potency and specificity. Supramolecular chemistry has only lately become recognized as a promising method to modify protein activities. In this review, we highlight recent advances in the use of supramolecular modification approaches in cancer therapy. We make special note of efforts to apply supramolecular modifications, such as molecular tweezers, to targeting the nuclear export signal (NES), which can be used to attenuate signaling processes in carcinogenesis. Finally, we discuss the strengths and weaknesses of using supramolecular approaches to targeting PPIs.

Identification of HER2 inhibitors from curcumin derivatives using combination of in silico screening and molecular dynamics simulation.

Breast cancer remains a major world health challenge in women. Some Breast cancers are human epidermal growth factor receptor 2 (HER2) positive. Since this protein promotes the growth of cancer cells, it remains a therapeutic target for novel drugs. This study uses in silico model to predict HER2 inhibitors from curcumin derivatives via QSAR, e-pharmacophore, ADMET as well as structure-based virtual screening using Schrodinger suite. The molecular dynamics simulation of lead compounds, reference ligand and co-crystalized ligand was performed using GROMACS. At the end, eight active curcumin derivatives were predicted as inhibitors of HER2 with high binding affinity and better interaction compared with the reference drug (Neratinib) but lower binding affinity compared with the co-crystalized ligand (TAK-285). After prediction of the bioactivity of the molecules using AutoQSAR, the hit compounds showed appreciable inhibitory pIC50 compared with the reference and co-crystalized ligands against HER2. The pharmacokinetics profile predicted the eight hit compounds as drug-like and drug candidates. The MD simulation predicted the stability of the two top-scored compounds (10763284 and 78321412) in complex with HER2 for the final 80 ns of the trajectory period after initial equilibration with higher H-bond interactions in the protein-reference drug complex compared to the hit compounds-HER2 complexes. This study revealed that curcumin derivatives especially (1E,6E)-1,8-bis(4-hydroxy-3-methoxyphenyl)octa-1,6-diene-3,5-dione and (1E,6E)-4-ethyl-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione were identified to demonstrate inhibitory activity against HER2 which is comparable to neratinib. Conclusively, the lead compounds require further in vitro and in vivo experimental validation for the discovery of new HER2 antagonists for breast cancer management.Communicated by Ramaswamy H. Sarma.

Computational investigation of phytochemicals from Abrus precatorius seeds as modulators of peroxisome proliferator-activated receptor gamma (PPARγ).

Type 2 diabetes mellitus remains global health challenge with involvement of both insulin resistance and dysfunctional insulin secretion from the pancreatic ß-cell. Currently, peroxisome proliferator-activated receptor gamma (PPARγ) has been established to play a significant role in glucose homeostasis and insulin sensitization contributing to the pathogenesis of type 2 diabetes mellitus. Hence, this study used in-silico analysis to predict PPARγ antagonists from the natural compounds. ADMET screening, structure-based virtual screening and MM/GBSA calculations of phytochemicals from HPLC analysis of A. precatorius seeds were performed against PPARγ using Maestro Schrodinger suite, followed by the MD simulation of top hit compounds and reference ligand using GROMACS. The quantum chemical calculations of the compounds were performed using Spartan 14 computational chemistry software. The five compounds showed varying degree of binding affinity against PPARγ, the post-docking analysis confirmed strong interaction against the amino acid residues of the binding site of the target. Chlorogenic acid showed the highest docking score (-10.719 kcal/mol) among the compounds comparable to the reference ligand (acarbose = -10.634 kcal/mol). Additionally, MM/GBSA binding free energy (ΔGbind) calculations support the modulatory potential for the docked compounds, which exclusively revealed the highest binding energy for the compounds than the reference ligand (acarbose). The MD simulations suggested the stability of Chlorogenic acid and Quercetin in complex with PPARγ at least in the time period of 90 ns after initial equilibration state with more H-bond observed between the target-hit compounds complex compared to the Acarbose-PPARγ complex. ADMET profile revealed that the five compounds were favorably druggable and promising drug candidates. The quantum chemical calculations showed that the compounds possess better bioactivity and chemical reactivity with favorable intra-molecular charge transfer as electron-donor and electron-acceptor. This study revealed that bioactive compounds especially chlorogenic acid and quercetin identified from A. precatorius seeds demonstrated good modulatory potential against PPARγ compared to acarbose. Therefore, these compounds require further experimental validation for the discovery of new antagonist of PPARγ for developing new anti-diabetes therapy.Communicated by Ramaswamy H. Sarma.

Discovery of putative inhibitors against main drivers of SARS-CoV-2 infection: Insight from quantum mechanical evaluation and molecular modeling.

SARS-CoV-2 triggered a worldwide medical crisis, affecting the world's social, emotional, physical, and economic equilibrium. However, treatment choices and targets for finding a solution to COVID-19's threat are becoming limited. A viable approach to combating the threat of COVID-19 is by unraveling newer pharmacological and therapeutic targets pertinent in the viral survival and adaptive mechanisms within the host biological milieu which in turn provides the opportunity to discover promising inhibitors against COVID-19. Therefore, using high-throughput virtual screening, manually curated compounds library from some medicinal plants were screened against four main drivers of SARS-CoV-2 (spike glycoprotein, PLpro, 3CLpro, and RdRp). In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized Born surface area) analysis, molecular dynamics (MD) simulation, and drug-likeness screening were performed to identify potential phytodrugs candidates for COVID-19 treatment. In support of these approaches, we used a series of computational modeling approaches to develop therapeutic agents against COVID-19. Out of the screened compounds against the selected SARS-CoV-2 therapeutic targets, only compounds with no violations of Lipinski's rule of five and high binding affinity were considered as potential anti-COVID-19 drugs. However, lonchocarpol A, diplacol, and broussonol E (lead compounds) were recorded as the best compounds that satisfied this requirement, and they demonstrated their highest binding affinity against 3CLpro. Therefore, the 3CLpro target and the three lead compounds were selected for further analysis. Through protein-ligand mapping and interaction profiling, the three lead compounds formed essential interactions such as hydrogen bonds and hydrophobic interactions with amino acid residues at the binding pocket of 3CLpro. The key amino acid residues at the 3CLpro active site participating in the hydrophobic and polar inter/intra molecular interaction were TYR54, PRO52, CYS44, MET49, MET165, CYS145, HIS41, THR26, THR25, GLN189, and THR190. The compounds demonstrated stable protein-ligand complexes in the active site of the target (3CLpro) over a 100 ns simulation period with stable protein-ligand trajectories. Drug-likeness screening shows that the compounds are druggable molecules, and the toxicity descriptors established that the compounds demonstrated a good biosafety profile. Furthermore, the compounds were chemically reactive with promising molecular electron potential properties. Collectively, we propose that the discovered lead compounds may open the way for establishing phytodrugs to manage COVID-19 pandemics and new chemical libraries to prevent COVID-19 entry into the host based on the findings of this computational investigation.

Structure-based discovery of selective CYP17A1 inhibitors for Castration-resistant prostate cancer treatment.

Prostate cancer (PCa) is the most common malignancy found in men and the second leading cause of cancer-related death worldwide. Castration-resistant PCa (CRPC) is defined by PCa cells that stop responding to hormone therapy. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) plays a critical role in the biosynthesis of androgens in humans. Androgen signaling cascade is a principal survival pathway for PCa cells and androgen-deprivation therapy (ADT) remains the key treatment for patients marked with locally advanced and metastatic PCa cells. Available synthetic drugs have been reported for toxicity, drug resistance, and decreasing efficacy. Thus, the design of novel selective inhibitors of CYP17A1 lyase would help circumvent associated side effects and improve pharmacological activities. Therefore, we employed structural bioinformatics techniques via molecular docking; molecular mechanics generalized born surface area (MM-GBSA), molecular dynamics (MD) simulation, and pharmacokinetic study to identify putative CYP17A1 lyase inhibitors. The results of the computational investigation showed that the Prunus dulcis compounds exhibited higher binding energy than the clinically approved abiraterone acetate. The stability of the ligand with the highest binding affinity (quercetin-3-o-rutinoside) was observed during MD simulation for 10 ns. Quercetin-3-o-rutinoside was observed to be stable within the active site of CYP17A1Lyase throughout the simulation period. The result of the pharmacokinetic study revealed that these compounds are promising therapeutic agents. Collectively, this study proposed that bioactive compounds from P. dulcis may be potential selective inhibitors of CYP17A1Lyase in CRPC treatments.

Computational Evaluation of Bioactive Compounds from Colocasia affinis Schott as a Novel EGFR Inhibitor for Cancer Treatment.

INTRODUCTION: Epidermal growth factor receptor (EGFR) is a transmembrane protein that belongs to the ErbB/HER-family of tyrosine kinase receptors. Somatic mutations and overexpression of EGFR have been reported to play a vital role in cancer cell development and progression, including cell proliferation, differentiation, angiogenesis, apoptosis, and metastatic spread. Hence, EGFR is an important therapeutic target for the treatment of various types of epithelial cancers. Somatic mutations have led to resistance to clinically approved synthetic EGFR inhibitors. Furthermore, synthetic EGFR inhibitors have been associated with several side effects. Thus, there is a need to develop novel EGFR inhibitors with an acceptable biosafety profile and high efficacy. METHODS: Herein, we employed structural bioinformatics and theoretical chemistry techniques via molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) calculation, density functional theory analysis (DFT), and pharmacokinetic study to identify novel EGFR inhibitors. RESULTS: The stringent molecular docking and MM-GBSA calculations identified MET 793, LYS 745, PHE 723, ASP 855, ARG 411, and THR 854 as principal amino acid residues for EGFR-ligands interactions. Furthermore, Colocasia affinis Schott compounds exhibited higher binding energy and more stable interactions than the reference compound (gefitinib). DFT analysis also ascertains better bioactivity and chemical reactivity of C. affinis Schott with favorable intramolecular charge transfer between electron-donor and electron acceptor groups. The pharmacokinetic profile of C. affinis Schott bioactive compounds satisfies Lipinski's rule of five assessment. CONCLUSION: Collectively, C. affinis Schott compounds demonstrated higher inhibitory potentials against EGFR and better pharmacological properties when compared with gefitinib. C. affinis Schott compounds are therefore suggested as promising therapeutic EGFR inhibitors for cancer treatment.