Repurposing of approved drugs for targeting CDK4/6 and aromatase protein using molecular docking and molecular dynamics studies.

Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast cancer, estrogen-receptor positive (ER+) is the most diagnosed. Estrogen upregulates cyclin D1, which in turn promotes the activity of CDK4/6 and facilitates cell cycle progression. To address this, the first-line treatment for ER+ breast cancer focuses on inhibiting estrogen production by targeting aromatase, the enzyme responsible for the rate-limiting step in estrogen synthesis. Thus, combining CDK4/6 inhibitors with aromatase inhibitors has emerged as a crucial treatment strategy for this type of breast cancer. This approach effectively suppresses estrogen biosynthesis and controls uncontrolled cell proliferation, significantly improving overall survival rates and delayed disease progression. This study aimed to identify compounds that are likely to inhibit CDK4/6 and aromatase simultaneously by using a structure-based drug design strategy. 12,432 approved and investigational drugs were prepared and docked into the active site of CDK6 using HTVS and XP docking modes of Glide resulting in 277 compounds with docking scores ≤ -7 kcal/mol. These compounds were docked into aromatase enzyme using XP mode to give seven drugs with docking scores≤ -6.001 kcal/mol. Furthermore, the shortlisted drugs were docked against CDK4 showing docking scores ranging from -3.254 to -8.254 kcal/mol. Moreover, MM-GBSA for the top seven drugs was calculated. Four drugs, namely ellagic acid, carazolol, dantron, and apomorphine, demonstrated good binding affinity to all three protein targets CDK4/6 and aromatase. Specifically, they exhibited favourable binding free energy with CDK6, with values of -51.92, -53.90, -50.22, and -60.97 kcal/mol, respectively. Among these drugs, apomorphine displayed the most favourable binding free energy with all three protein targets. To further evaluate the stability of the interaction, apomorphine was subjected to a 100 ns molecular dynamics simulation with CDK6. The results indicated the formation of a stable ligand-protein complex. While the results obtained from the MM-GBSA calculation of the binding free energies of the MD conformations of apomorphine showed less favourable binding free energy compared to that obtained post-docking. All these computational findings will provide better structural insight for the development of CDK4/6 and aromatase multi-target inhibitors.

Exploring the potential of approved drugs for triple-negative breast cancer treatment by targeting casein kinase 2: Insights from computational studies.

Triple-negative breast cancer (TNBC) is an aggressive malignancy that requires effective targeted drug therapy. In this study, we employed in silico methods to evaluate the efficacy of seven approved drugs against human ck2 alpha kinase, a significant modulator of TNBC metastasis and invasiveness. Molecular docking revealed that the co-crystallized reference inhibitor 108600 achieved a docking score of (-7.390 kcal/mol). Notably, among the seven approved drugs tested, sunitinib, bazedoxifene, and etravirine exhibited superior docking scores compared to the reference inhibitor. Specifically, their respective docking scores were -10.401, -7.937, and -7.743 kcal/mol. Further analysis using MM/GBSA demonstrated that these three top-ranked drugs possessed better binding energies than the reference ligand. Subsequent molecular dynamics simulations identified etravirine, an FDA-approved antiviral drug, as the only repurposed drug that demonstrated a stable and reliable binding mode with the human ck2 alpha protein, based on various analysis measures including RMSD, RMSF, and radius of gyration. Principal component analysis indicated that etravirine exhibited comparable stability of motion as a complex with human ck2 alpha protein, similar to the co-crystallized inhibitor. Additionally, Density functional theory (DFT) calculations were performed on a complex of etravirine and a representative gold atom positioned at different sites relative to the heteroatoms of etravirine. The results of the DFT calculations revealed low-energy complexes that could potentially serve as guides for experimental trials involving gold nanocarriers of etravirine, enhancing its delivery to malignant cells and introducing a new drug delivery route. Based on the results obtained in this research study, etravirine shows promise as a potential antitumor agent targeting TNBC, warranting further investigation through experimental and clinical assessments.

Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin's Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles.

Non-Hodgkin's lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin's lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin's lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between -7.66 and -8.42 Kcal/mol. The docking analysis of ligand-receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with -52.22 Kcal/mol. To identify the structural changes and the complexes' stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand-protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with -29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies.

Breast cancer (BC) is one of the main types of cancer that endangers women's lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.

Cytosporone E analogues as BRD4 inhibitors for cancer treatment: molecular docking and molecular dynamic investigations.

Cancer is considered one of the worldwide life-threatening and leading causes of human mortality. In 2020, 19,292,789 cancer cases and 9,958,133 cancer deaths have been estimated worldwide. Therefore, efforts have been devoted to discover novel anticancer agents. Bromodomains have a vital role in the regulation of transcription. Many reports have shown that bromodomain-containing protein 4 (BRD4) is an important target for cancer therapeutics. In this study, several in silico approaches were utilized to discover new inhibitors against the BRD4 protein using the Schrodinger suite. A library of 27 cytosporone E derivatives was docked into the active site of the BRD4 protein. Docked ligands showed docking scores ranging between -11.289 to -3.992 Kcal/mol. Ligands 1-4 showed better binding affinities with docking scores ranging from -11.289 to -8.917 Kcal/mol compared to the reference ligand BI-2536 (-8.426 Kcal/mol). These ligands displayed favorable MM-GBSA free binding energy. Also, ligands 1-4 were subjected to molecular dynamics simulations for 100 ns to get insight into the ligand-binding stability. These compounds exhibited an average RMSD below 2.8 Å, indicating the stability of the compounds with BRD4 protein. Further, Moreover, ligands 1-3 displayed favorable AMDET properties (absorption, distribution, metabolism, excretion, and toxicity). These new compounds might be potential leads to combat cancer.Communicated by Ramaswamy H. Sarma.

Phthalide derivatives as dihydrofolate reductase inhibitors for malaria: molecular docking and molecular dynamics studies.

Plasmodium falciparum dihydrofolate reductase enzyme (P. falciparum DHFR) is one of the vital drug targets for malaria treatment, as this protein is indispensable for nucleotide metabolic pathways. This research aimed to discover promising phthalide derivatives against both wild and mutant P. falciparum DHFR enzymes through various computational techniques. The binding affinities were investigated using molecular docking, which showed five compounds having the highest affinity scores against both enzymes compared to the reference compounds. MM-GBSA calculations displayed favourable free binding energy. Moreover, the ADMET properties of the compounds are within acceptable ranges. The stability of the ligand-protein complexes was studied by Molecular Dynamics (MD) simulations. Depending on the results obtained from this research, we propose three compounds to be hit against P. falciparum DHFR activity which could be examined experimentally.Communicated by Ramaswamy Sarma.

Drug repurposing against main protease and RNA-dependent RNA polymerase of SARS-CoV-2 using molecular docking, MM-GBSA calculations and molecular dynamics.

A virus called severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) is the causing organism of coronavirus disease 2019 (COVID-19), which has severely affected human life and threatened public health. The pandemic took millions of lives worldwide and caused serious negative effects on human society and the economy. SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) are interesting targets due to their crucial role in viral replication and growth. Since there is only one approved therapy for COVID-19, drug repurposing is a promising approach to finding molecules with potential activity against COVID-19 in a short time and at minimal cost. In this study, virtual screening was performed on the ChEMBL library containing 9923 FDA-approved drugs, using various docking filters with different accuracy. The best drugs with the highest docking scores were further examined for molecular dynamics (MD) studies and MM-GBSA calculations. The results of this study suggest that nadide, cangrelor and denufosol are promising potential candidates against COVID-19. Further in vitro, preclinical and clinical studies of these candidates would help to discover safe and effective anti-COVID-19 drugs.

Drug repurposing for SARS-CoV-2 main protease: Molecular docking and molecular dynamics investigations.

The current novel corona virus illness (COVID-19) is a developing viral disease that was discovered in 2019. There is currently no viable therapeutic strategy for this illness management. Because traditional medication development and discovery has lagged behind the threat of emerging and re-emerging illnesses like Ebola, MERS-CoV, and, more recently, SARS-CoV-2. Drug developers began to consider drug repurposing (or repositioning) as a viable option to the more traditional drug development method. The goal of drug repurposing is to uncover new uses for an approved or investigational medicine that aren't related to its original use. The main benefits of this strategy are that there is less developmental risk and that it takes less time because the safety and pharmacologic requirements are met. The main protease (Mpro) of corona viruses is one of the well-studied and appealing therapeutic targets. As a result, the current research examines the molecular docking of Mpro (PDB ID: 5R81) conjugated repurposed drugs. 12,432 approved drugs were collected from ChEMBL and drugbank libraries, and docked separately into the receptor grid created on 5R81, using the three phases of molecular docking including high throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP). Based on docking scores and MM-GBSA binding free energy calculation, top three drugs (kanamycin, sulfinalol and carvedilol) were chosen for further analyses for molecular dynamic simulations.

Identification of novel transmembrane Protease Serine Type 2 drug candidates for COVID-19 using computational studies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emergence has resulted in a global health crisis. As a consequence, discovering an effective therapy that saves lives and slows the spread of the pandemic is a global concern currently. In silico drug repurposing is highly regarded as a precise computational method for obtaining fast and reliable results. Transmembrane serine-type 2 (TMPRSS2) is a SARS CoV-2 enzyme that is essential for viral fusion with the host cell. Inhibition of TMPRSS2 may block or lessen the severity of SARS-CoV-2 infection. In this study, we aimed to perform an in silico drug repurposing to identify drugs that can effectively inhibit SARS-CoV-2 TMPRSS2. As there is no 3D structure of TMPRSS2 available, homology modeling was performed to build the 3D structure of human TMPRSS2. 3848 world-approved drugs were screened against the target. Based on docking scores and visual outcomes, the best-fit drugs were chosen. Molecular dynamics (MD) and density functional theory (DFT) studies were also conducted. Five potential drugs (Amikacin, isepamicin, butikacin, lividomycin, paromomycin) exhibited promising binding affinities. In conclusion, these findings empower purposing these agents.