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

Chukwuemeka, Prosper Obed; Umar, Haruna Isiyaku; Iwaloye, Opeyemi; Oretade, Oluwaseyi Matthew; Olowosoke, Christopher Busayo; Oretade, Oyeyemi Janet; Elabiyi, Michael Omoniyi

doi:10.1080/07391102.2021.1913231

Cited by 13 publications

(5 citation statements)

References 35 publications

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“…This does not eliminate the other dietary phytochemicals as good candidates for anti-brotic drug discovery, design and development. Thus, it opens an avenue for precise structural optimization methodology to enhance these unfavourable features while maintaining excellent inhibitory performance [51].…”

Section: Discussionmentioning

confidence: 99%

Uterine Fibroids allied protein lockage; An endpoint for medicinal compounds target via the computer-aided route to evade myomectomy

Olowosoke,

Eze,

Munir

et al. 2023

Preprint

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Beyond the pains of pregnancy, miscarriages and other child-bearing risks associated with the pride of motherhood, Uterine fibroids (UFs) are another significant reproductive age detriment in women’s health. These tumours are often challenging to detect in the early stage until they become large outgrowth which always requires surgical removal to mitigate risks. However, with the understanding of alteration in the complex signalling pathways, specific proteins connected in this rapid outgrown have been identified, and some studies have been reported on dietary phytochemicals’ potency to halt the growth. Consequently, this computer-aided study explores this class of phytochemicals as inhibitors of five specific UFs targets (estrogen receptor protein (ESR), epidermal growth factor receptor protein (EGFR), insulin-like growth factor 1 receptor (IGF-1R), progesterone receptor (PGR), and Yes1 Associated protein (YAP1)). During the screening, the gene-disease association revealed a correlation between these proteins to six reproductive conditions including UFs with a 0 to 1 evidence index. The molecular docking and molecular mechanics’ free energy combined with Generalized Born and surface area showed comparable close points in the regression line supporting the binding affinity of dietary phytochemicals to the mapped proteins’ active site. Overall, more than 50% of the phytochemicals exhibit good pharmacokinetic, drug-likeness and ADMET profiles as compared to the standard drugs and co-ligands. Hence, their PASS bioactivity supports anti-cancer potential with a good Pa > Pi ratio, and they have stable and less reactivity from the quantum mechanical calculation. Ultimately, these phytochemicals are proposed for further experimental evaluation for efficacy in managing and treating UFs.

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Section: Discussionmentioning

confidence: 99%

Uterine Fibroids allied protein lockage; An endpoint for medicinal compounds target via the computer-aided route to evade myomectomy

Olowosoke,

Eze,

Munir

et al. 2023

Preprint

Self Cite

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“…Notably, geometric pre-optimization of the top four inhibitors was carried out using the molecular mechanics force field (MMFF94) integrated with the Avogadro v 1.2.0 software program ( Hanwell et al, 2012 ), coupled with chemical structure protonation at a pH of 7.4. The pre-optimized geometry serves as a query for QM calculation ( Chukwuemeka et al, 2021 ). A Broyden–Fletcher–Goldfarb–Shanno (BFGS) geometry optimizer was used for structure minimization and optimization at the semi-empirical theory level.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Notably, geometric pre-optimization of the top four inhibitors were carried out using the molecular mechanics force eld (MMFF94) integrated in Avogadro v1.2.0 software program (29), coupled chemical structure protonation at a pH of 7.4. The pre-optimized geometry serves as query for QM calculation (30). Broyden-Fletcher-Goldfarb-Shanno (BFGS) geometry optimizer was employed for structure minimization and optimization at semi-empirical theory level.…”

Section: Quantum Mechanical Calculationmentioning

confidence: 99%

Discovery of Promising Inhibitors for SARS-CoV-2 Therapeutic Targets: A Quantum Mechanics and Molecular Modeling study

Balogun

Chukwudozie

Ogbodo

et al. 2022

Preprint

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SARS-CoV-2 triggers 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 limiting. A viable approach to combating the threat of COVID-19 is to create pharmacological and therapeutic targets by uncovering promising inhibitors and proteins in the viral life cycle of COVID-19. Therefore, in this study, we employ high-throughput virtual screening to screen library of phytocompounds from selected medicinal plants targeting SARS-CoV-2 spike glycoprotein, 3CLpro, PLpro and RdRp. Virtual screening approach have been reported as a promising method to identify biologically active compounds from large libraries. In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized born surface area) analysis, molecular dynamics (MD) simulation and pharmacokinetic/drug-likeness model was performed to identify potential phytodrugs. In support to these approaches, we employ series of chemical quantum calculation, semi empirical Hamiltonian and density functional theory analysis to develop therapeutic agents against COVID-19. We propose that the discover therapeutic targets/molecules may open the way for the establishment of phytodrugs for the management of COVID-19 pandemics and new chemical libraries for preventing COVID-19 entry into the host, based on the findings of this integrated computational investigation.

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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

Cited by 13 publications

References 35 publications

Uterine Fibroids allied protein lockage; An endpoint for medicinal compounds target via the computer-aided route to evade myomectomy

Uterine Fibroids allied protein lockage; An endpoint for medicinal compounds target via the computer-aided route to evade myomectomy

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

Discovery of Promising Inhibitors for SARS-CoV-2 Therapeutic Targets: A Quantum Mechanics and Molecular Modeling study

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