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Introduction: Heterogeneous Acute Myeloid Leukemia (AML) causes substantial worldwide morbidity and death. AML is characterized by excessive proliferation of immature myeloid cells in the bone marrow and impaired apoptotic regulator expression., Method: B-Cell Lymphoma 2 (BCL-2), an anti-apoptotic protein overexpressed in AML, promotes leukemic cell survival and chemoresistance. Thus, reducing BCL-2 may treat AML. Anticancer activities are found in Aloe barbadensis Miller (Aloe vera). Thus, this work used molecular modeling to assess Aloe vera bioactive chemicals as BCL-2 inhibitors. Molecular docking simulation showed that all identified Aloe vera phytocompounds have strong BCL-2 binding affinities (-6.7 to -8.7 kcal/mol)., Result: Campesterol and α-tocopherol were identified as promising compounds for BCL-2 inhibitor research based on their drug-likeness, pharmacokinetics, and toxicity profiles. The stability and conformational of the BCL-2-compound complexes showed that the compounds were stable in BCL-2's binding pocket., Conclusion: Campesterol and α-tocopherol are promising BCL-2 inhibitors that might become effective anti-leukemic therapies with additional in vitro and in vivo research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cancer remains a formidable challenge in therapeutic development owing to its complex molecular mechanisms and resistance to conventional treatments. Recent evidence suggests that TOE1 may play a role in cancer progression, making it an attractive target for therapeutic interventions, nevertheless, very limited research in literature has explored the potential of TOE1 inhibitors as anti-cancer. Herein, by exploring a library of 13,900 cysteine-targeted covalent inhibitors via a comprehensive virtual screening process, we sought to identify potential compounds that could be developed into effective cancer therapies against TOE1. The compounds were first screened based on their binding affinity, followed by their compliance with drug-like properties, and finally, by their effective covalent modeling to a reactive cysteine (Cys80). A total of 66 compounds, 28 compounds, and 3 compounds were found to have higher binding affinities, optimum drug-likeness, and higher covalent docking scores, respectively, than the reference compound. The top three screened compounds, 0462, 2204, and 7034, demonstrated favorable interaction profiles, covalent binding dynamics, free binding energetics, and per-residue energy contributions as compared to the reference compound. Notably, compound 0462 contributed to the highest free binding energy and significantly enhanced the stability and rigidity of TOE1, while restricting residue flexibility. This study provides an account of the molecular mechanics underpinning the covalent inhibition of TOE1, while providing a compelling case for further investigation and translation of the screened TOE1 inhibitors, particularly compound 0462, as novel therapeutics against cancer.

Genetic alterations of the genes encoding the isocitrate dehydrogenase (IDH) enzymes have been identified in about 20% of acute myeloid leukemia (AML) cases as well as many other forms of cancers. Notable among these alterations are the neomorphic IDH1_R132H and IDH2_R140Q mutations which lead to the production of an oncometabolite. Hence, their inhibition is widely considered a therapeutic strategy in the treatment of many cancers. While many inhibitors of the mutant enzymes have been developed, an inhibitor that is capable of co-inhibiting both enzymes are currently lacking while drug resistance has also limited the clinical usage of previously identified mono inhibitors. Consequently, this study employed molecular modeling approaches, such as molecular docking, molecular mechanics generalized Born Surface area (MM/GBSA), molecular dynamics (MD) simulation, and density functional theory (DFT) analysis to identify potential dual inhibitors of the previously mentioned mutant IDH1/2 from the phytocompounds of Phyllantus amarus . Of the 31 phytocompounds identified, 20 showed good binding affinities for both IDH1 _R132H and IDH2 _R140Q (ranging from -5.2 Kca/mol to -9.6 Kcal/mol) and had desirable pharmacokinetic properties. However, ellagic acid and pinoresinol possessed better pharmacokinetic properties, rendering suitable hits. Investigation of the behavior of the IDH1_R132H and IDH2_R140Q complexes with ellagic acid and pinoresinol via the RMSD, RMSF, and contact map analyses showed that all the complexes-maintained stability throughout the simulation time. Ultimately, ellagic acid and pinoresinol were identified as promising hits for the development of IDH1_R132H and IDH2_R140Q dual inhibitors. However, further experimental studies are needed to confirm their potential as therapies.Communicated by Ramaswamy H. Sarma.

Protein-protein interactions, or PPIs, are a part of every biological activity and have been linked to a number of diseases, including cancer, infectious diseases, and neurological disorders. As such, targeting PPIs is considered a strategic and vital approach in the development of new medications. Nonetheless, the wide and flat contact interface makes it difficult to find small-molecule PP inhibitors. An alternative strategy would be to use the PPI interaction motifs as building blocks for the design of peptide-based inhibitors. Herein, we designed 12-mer peptide inhibitors to target p25-inducing-cyclin-dependent kinase (Cdk5) hyperregulation, a PPI that has been shown to perpetuate neuroinflammation, which is one of the major causal implications of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. We generated a library of 5 062 500 peptide combination sequences (PCS) derived from the interaction motif of Cdk5/p25 PP interface. The 20 amino acids were differentiated into six groups, namely, hydrophobic (aliphatic), aromatic, basic, acidic, unique, and polar uncharged, on the basis of their physiochemical properties. To preserve the interaction motif necessary for ideal binding, de novo modeling of all possible peptide sequence substitutions was considered. A set of filters, backed by the Support Vector Machine (SVM) algorithm, was then used to create a shortlisted custom peptide library that met specific bioavailability, toxicity, and therapeutic relevance, leading to a refined library of 15 PCS. A greedy algorithm and coarse-grained force field were used to predict peptide structure and folding before subsequent modeling studies. Molecular docking was performed to estimate the relative binding affinities, and out of the top hits, Pep15 was subjected to molecular dynamics simulations and binding free-energy calculations in comparison to a known peptide inhibitor with experimental data (template peptide). Interestingly, the identified peptide through our protocol, Pep15, was found to show a significantly higher binding affinity than the reference template peptide (-48.10 ± 0.23 kcal/mol and -17.53 ± 0.27 kcal/mol, respectively). In comparison to the template peptide, Pep15 was found to possess a more compact and buried surface area, tighter binding landscape, and reduced conformational variability, leading to enhanced structural and kinetic stability of the Cdk5/p25 complex. Notably, both peptide inhibitors were found to have a minimal impact on the architectural integrity of the Cdk5/p25 secondary structure. Herein, we propose Pep15 as a novel and potentially disruptive peptide drug for Cdk5/p25-mediated neurodegenerative phenotypes that require further clinical investigation. The systematic protocol and findings of this report would serve as a valuable tool in the identification of critical PPI interface reactive residues, designing of analogs, and identification of more potent peptide-based PPI inhibitors., (© 2024 The Author(s). Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases., (© 2024 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)