Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Unveiling fructose and glucose binding to human serum albumin: fluorescence measurements and docking, molecular dynamics and quantum biochemistry computations.

This research examines the interaction between human serum albumin (HSA) and various sugar forms (ß-D-fructofuranose (FRC), α-D-glucopyranose (GLC), Keto-D-fructose (FRO), Aldehydo-D-glucose (GLO), and modified Aldehydo-D-glucose (GLOm)) using fluorescent spectroscopy, molecular docking simulations, molecular dynamics, protein conformational clusters (EnGens), molecular fractionation with conjugate caps (MFCC) and quantum biochemistry analysis. We analyze molecular and quantum aspects, uncovering interaction energies between sugar atoms and amino acids. Total interaction energy considers protein fragmentation, energetic decomposition, and interaction energy from a bottom-up perspective. Molecular dynamics reveal that unmodified Aldehydo-D-glucose (GLO) escapes HSA binding sites, explaining gradual glycation. We pioneer studying HSA's binding mechanism with glucose and fructose in a 1:1 ratio using long molecular dynamics simulations. Results suggest the transitional GLOm form has a higher Sudlow I site propensity than unmodified glucose, crucial for K195 glycation. FRO and GLOm interaction tendencies move toward a deeper FA7 cavity, near its center. This approach effectively elucidates small molecule binding mechanisms, consistent with previous experimental results.Communicated by Ramaswamy H. Sarma.

Noncovalent binding of carbofuran to acetylcholinesterase from Homo sapiens, Danio rerio, Apis mellifera and Caenorhabditis elegans: Homology modelling, molecular docking and dynamics, and quantum biochemistry description.

Although various regulatory agencies have banned or severely restricted the use of carbofuran (CAR), recent reports indicate the presence of CAR residues in both cultivated and wild areas. This pesticide is a potent inhibitor of acetylcholinesterase (AChE), which acts by preventing the hydrolysis of acetylcholine (ACh). Given the critical role of AChE::ACh in the proper functioning of the nervous system, we thought it appropriate to investigate the binding of CAR to AChEs from Homo sapiens, Danio rerio, Apis mellifera, and Caenorhabditis elegans using homology modelling, molecular docking, molecular dynamics, and quantum biochemistry. Molecular docking and dynamics results indicated peculiar structural behavior in each AChE::CAR system. Quantum biochemistry results showed similar affinities for all complexes, confirming the description of carbofuran as a broad-spectrum pesticide, and have a limited correlation with IC50 values. We found the following decreasing affinity order of AChE species: H. sapiens > A. mellifera > C. elegans > D. rerio. The computational results suggest that CAR occupies different pockets in the AChEs studied. In addition, our results showed that CAR binds to hsAChE and ceAChE in a very similar manner: it has high affinities for the same subsites in both species and forms hydrogen bonds with residues (hsTYR124 and ceTRP107) occupying homologous positions in the peripheral site. This suggests that this nematode is a potential model to evaluate the toxicity of carbamates, even though the sequence identity between them is only 41 %. Interestingly, we also observed that the catalytic histidines of drAChE and amAChE exhibited favorable contacts with carbofuran, suggesting that the non-covalent binding of carbofuran to these proteins may promote faster carbamylation rates than the binding modes to human and worm acetylcholinesterases. Our computational results provide a better understanding of the binding mechanisms in these complexes, as well as new insights into the mechanism of carbamylation.

Pharmacokinetic Profile Evaluation of Novel Combretastatin Derivative, LASSBio-1920, as a Promising Colorectal Anticancer Agent.

LASSBio-1920 was synthesized due to the poor solubility of its natural precursor, combretastatin A4 (CA4). The cytotoxic potential of the compound against human colorectal cancer cells (HCT-116) and non-small cell lung cancer cells (PC-9) was evaluated, yielding IC50 values of 0.06 and 0.07 µM, respectively. Its mechanism of action was analyzed by microscopy and flow cytometry, where LASSBio-1920 was found to induce apoptosis. Molecular docking simulations and the enzymatic inhibition study with wild-type (wt) EGFR indicated enzyme-substrate interactions similar to other tyrosine kinase inhibitors. We suggest that LASSBio-1920 is metabolized by O-demethylation and NADPH generation. LASSBio-1920 demonstrated excellent absorption in the gastrointestinal tract and high central nervous system (CNS) permeability. The pharmacokinetic parameters obtained by predictions indicated that the compound presents zero-order kinetics and, in a human module simulation, accumulates in the liver, heart, gut, and spleen. The pharmacokinetic parameters obtained will serve as the basis to initiate in vivo studies regarding LASSBio-1920's antitumor potential.

Characterization of the binding interaction between atrazine and human serum albumin: Fluorescence spectroscopy, molecular dynamics and quantum biochemistry.

Atrazine (ATR), one of the most used herbicides worldwide, causes persistent contamination of water and soil due to its high resistance to degradation. ATR is associated with low fertility and increased risk of prostate cancer in humans, as well as birth defects, low birth weight and premature delivery. Describing ATR binding to human serum albumin (HSA) is clinically relevant to future studies about pharmacokinetics, pharmacodynamics and toxicity of ATR, as albumin is the most abundant carrier protein in plasma and binds important small biological molecules. In this work we characterize, for the first time, the binding of ATR to HSA by using fluorescence spectroscopy and performing simulations using molecular docking, classical molecular dynamics and quantum biochemistry based on density functional theory (DFT). We determine the most likely binding sites of ATR to HSA, highlighting the fatty acid binding site FA8 (located between subdomains IA-IB-IIA and IIB-IIIA-IIIB) as the most important one, and evaluate each nearby amino acid residue contribution to the binding interactions explaining the fluorescence quenching due to ATR complexation with HSA. The stabilization of the ATR/FA8 complex was also aided by the interaction between the atrazine ring and SER454 (hydrogen bond) and LEU481(alkyl interaction).

Molecular insight on the binding of stevia glycosides to bovine serum albumin.

The interaction of the steviol and its glycosides (SG), steviolbioside, and rebaudioside A, with bovine serum albumin (BSA) was studied by absorption and fluorescence spectroscopy techniques alongside molecular docking. The stevia derivatives quenched the fluorescence of BSA by a dynamic quenching mechanism, indicating the interaction between the stevia derivatives and BSA. The binding constant (Kb) of steviol was 100-1000-fold higher than those of SG. The stevia derivative/BSA binding reaction was spontaneous and involved the formation of hydrogen bonds and van der Waals interactions between steviol and steviolbioside with BSA, and water reorganization around the rebaudioside A/BSA complex. Molecular docking pointed out the FA1 and FA9 binding sites of BSA as the probable binding sites of steviol and SG, respectively. In conclusion, steviol enhanced hydrophobicity and small size compared to SG may favor its binding to BSA. As steviol and its glycosides share binding sites on BSA with free fatty acids and drugs, they may be competitively displaced from plasma albumin under various physiological states or disease conditions. These findings are clinically relevant and provide an insight into the pharmacokinetics and pharmacodynamics of the stevia glycosides.