Computational Studies for Development of Triazole‐Pyrimidines as Inhibitor of α‐Tubulin Receptor

Amidst the unprecedented 2019 coronavirus outbreak and the substantial loss of lives due to the scarcity of information about the virus and lack of viable drugs, understanding the impact of the nCoV Main Protease (Mpro) on the endocrine system has emerged as a critical topic to pursue. This study explores the potential interactions between four key hormones (cortisol, cortisone, estradiol, and estrone) and the Mpro of nCoV using various in‐silico methodologies. Density Functional Theory (DFT) calculations scrutinized the electron density delocalization of these hormones. Through molecular docking, the molecular‐level binding of Mpro of nCoV with these hormones was studied, revealing cortisol as the hormone exhibiting the most promising binding affinity (−100.05 kcal/mol). Furthermore, molecular dynamics (MD) simulations, emulating human body conditions at distinct temperatures, were employed to study the implications of these interactions. The study analysed the various trajectories such as root mean square deviation (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), and H‐bond trajectories to understand the potential impact on biological systems. The findings demonstrate the binding potential of the Mpro of nCoV with these hormones, raising plausible concerns regarding consequential physiological changes within the human body.

A Theoretical Study To Understand the Impact of Mpro of nCoV on the Hormones

Babu Singh,

Himani,

Yadav

et al. 2024

Discovery of a New Isatin Scaffold for BCR‐ABL Tyrosine Kinase Inhibitors Using a Comprehensive Computational Approach

EL Mchichi,

Alaqarbeh,

Lakhlifi

et al. 2024

Inserting Isatin (1H indole 2,3‐dione) stands out as an exceptionally captivating element in the realm of drug design and development. Hence, there has been a notable focus in numerous anticancer studies on investigating the potential of various derivatives of Isatin (1H indole 2,3‐dione), including imines, hydrazones, thiosemicarbazones, and other compounds. Therefore, to develop new compounds with anticipated high activity, a novel series of 40 Isatin derivatives have undergone 3D‐QSAR studies as potent anticancer agents against the leukemia cell line (K562). This approach has been pursued due to the significant importance placed on exploring the potential of these derivatives. Through the analysis of graphical contour maps, the generated models yielded favorable statistical outcomes and provided valuable insights into the structural elements that exert a significant influence on the activity. Furthermore, both CoMFA and CoMSIA models have shown suitable reliabilities (q2 = 0.689, 0.772, respectively) and predictive abilities (r2pred = 0.780, 0.892, respectively). As a result, the design of five new compounds (T1–T5) based on the Isatin moiety, which exhibited remarkable inhibitory activity, has successfully been accomplished. Accordingly, molecular docking and molecular dynamics (MD) simulations of 100 ns have been utilized to examine the interaction mechanism and conformational changes of the newly designed compounds at the binding site of BCR‐ABL tyrosine kinase. MD simulation revealed that both compounds T1 and T2 formed stable complexes with BCR‐ABL. Additionally, the assessment of the in‐silico pharmacokinetic parameters indicates favorable ADMET properties. These findings hold promise for the future development of potent BCR‐ABL tyrosine kinase inhibitors.

Identification of Potent CHK2 Inhibitors‐Modulators for Therapeutic Application in Cancer: A Machine Learning Integrated Fragment‐Based Drug Design Approach

Sudhir Kolpe,

Sardarsinh Suryawanshi,

Eldesoky

et al. 2024

The CHK2 protein regulates the cell division cycle and responds to DNA damage. Additionally, it facilitates the repair of DNA damage and maintains the integrity of its biological processes. Dysregulation of the CHK2 protein is associated with a predisposition to harmful diseases. The current research protocol was designed to identify novel hit molecules as CHK2 inhibitors and disrupt the normal biological function of the CHK2 protein via a fragment‐based drug discovery approach. The protocol involved generating fragments using the MacFrag tool, followed by a chemical similarity search utilizing RDKit to identify fragment molecules analogous to previously established CHK2 inhibitor scaffolds. The bioactive molecules were constructed using the Fragmenstein tool, followed by molecular docking simulations to investigate their binding affinity. In addition, pharmacokinetic properties were analyzed, and a molecular dynamics simulation study was conducted to assess the stability of selected compounds with CHK2 protein. Finally, five novel compounds were identified as excellent CHK2 inhibitors through the FBDD and show good binding interactions at active sites of CHK2 with beneficial ADMET properties. This research work presents novel CHK2 inhibitor molecules that have the potential to be utilized in drug discovery, serving as key leads for future advancements in healthcare industries and sectors.