Computational identification of potential acetylcholinesterase (AChE) and monoamine oxidase-B inhibitors from Vitis vinifera: a case study of Alzheimer's disease (AD).

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that affects people aged 60 years and above. Yet, the discovery of potent therapeutic agents against this disease has no utmost progress and a number of drug candidates could not make it out of the clinical trials at varied stages. At the same time, the currently available anti-cholinesterase (AChE) and monoamine oxidase-B (MAO-B) for the treatment of AD can only improve the clinical symptoms while the recently approved immunotherapy agent "remains questionable. Thus, the need for novel therapeutic agents with the potential to treat the aetiology of the disease. Herein, this study sought to examine the potential of a number of bioactive compounds derived from Vitis vinifera as a promising agent against AChE and MAO-B. Using a computational approach via molecular docking 23 bioactive agents were screened against AChE and MAO-B, and the compounds with a binding score below that of the standard ligand were further subjected to drug-likeness and pharmacokinetic screening. Eight and thirteen of the studied agents optimally saturated the active pocket of the AChE and MAO-B respectively, forming principal interactions with a number of amino acids at the active pocket of the targets and among these compounds only rutin failed the drug-likeness test by violating four parameters while all showed moderate pharmacokinetics features. A number of Vitis vinifera-derived bioactive compounds show excellent inhibitory potential against AChE and MAO-B, and moderate pharmacokinetic features when compared to the reference ligand (tacrine). These compounds are therefore proposed as novel AChE and MAO-B inhibitors for the treatment of AD and wet-lab analysis is necessary to affirm their potency.

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.

Identification of bioactive compounds from Vaccinium vitis-idaea L. (Lingonberry) as inhibitors for treating KRAS-associated cancer: a computational approach.

Lung cancer is the cancer of the lung's epithelial cells typically characterized by difficulty breathing, chest pain, blood-stained coughs, headache, and weight loss. If left unmanaged, lung cancer can spread to other body parts. While several treatment methods exist for managing lung cancer, exploring natural plant sources for developing therapeutics offers great potential in complementing other treatment approaches. In this study, we evaluated the bioactive compounds in Vaccinium vitis-idaea for treating KRAS-associated lung cancer types. In this study, we concentrated on inhibiting the mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) by targeting an associated protein (Phosphodiesterase 6δ) to which KRAS form complexes. We evaluated bioactive compounds from Lingonberry (Vaccinium vitis-idaea L.), adopting computational approaches such as molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, and pharmacokinetics analysis. A total of 26 out of 39 bioactive compounds of Vaccinium vitis-idaea L. had a higher binding affinity to the target receptor than an approved drug, Sotorasib. Also, further analyses of all lead/top compounds in this study identified (+)-Catechin (Cianidanol), Arbutin, Resveratrol, and Sinapic acid, to be potential drug candidates that could be pursued. In sum, Arbutin, (+)-Catechin, and Sinapic acid are predicted to be the top compound of Vaccinium vitis-idaea L. because of their pharmacokinetic properties and drug-likeness attributes. Also, their stability to the target receptor makes them a potential drug candidate that could be explored for treating KRAS mutation-associated lung cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00165-1.

Identification of apposite antagonist for androgen receptor in prostate cancer: an in silico study of fenugreek compounds.

Benign Prostate Cancer (BPC), a prevalent condition predominantly affecting elderly males, manifests with voiding difficulties and urinary retention. A library of compounds from Trigonella foenum-graecum, commonly known as fenugreek was used in this study. We aimed to explore its potential anti-cancer effects by computationally assessing its inhibitory activity on the androgen receptor (AR). For in-silico drug assessment, we employed Maestro 12.8, part of the Schrödinger Suite, to identify the most promising candidates acting as androgen receptor antagonists in the treatment of BPC. Subsequently, 59 fenugreek compounds were retrieved from the PubChem database and subjected to molecular docking against the active site of the target protein, 1E3G. 100-nanosecond molecular dynamics (MD) simulations were performed to assess the stability and compactness of the AR-ligand complexes. Notably, the AR-kaempferol complex exhibited the least fluctuation within the AR active site throughout the simulation trajectory, followed by chlorogenic acid and the reference ligand, hydroxyflutamide. The MM/GBSA values revealed the compounds' maximum free binding energy (-103.3 ± 6, -87.4 ± 23, -68.5 ΔGbind) for chlorogenic acid, kaempferol, and hydroxyflutamide, respectively. These findings suggest their potential as promising leads for drug development. Further lead optimization and comprehensive studies on the top-ranked ligands identified in this investigation are warranted to advance their potential as therapeutic agents for BPC treatment.Communicated by Ramaswamy H. Sarma.

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.

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.

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.