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In silico studies were performed to assess the binding affinity of selected organophosphorus compounds toward the acetylcholinesterase enzyme (AChE). Quantum mechanical calculations, molecular docking, and molecular dynamics (MD) with molecular mechanics Generalized–Born surface area (MM/GBSA) were applied to assess quantitatively differences between the binding energies of acetylcholine (ACh; the natural agonist of AChE) and neurotoxic, synthetic correlatives (so-called "Novichoks", and selected compounds from the G- and V-series). Several additional quantitative descriptors like root-mean-square fluctuation (RMSF) and the solvent accessible surface area (SASA) were briefly discussed to give—to the best of our knowledge—the first quantitative in silico description of AChE—Novichok non-covalent binding process and thus facilitate the search for an efficient and effective treatment for Novichok intoxication and in a broader sense—intoxication with other warfare nerve agents as well. [ABSTRACT FROM AUTHOR]

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties. [ABSTRACT FROM AUTHOR]

Bisphosphonates constitute a group of pyrophosphate analogues therapeutically active against bone diseases. Numerous studies confirm their anticancer and antimetastatic potential as well as ability to relieve pathological pain. Although this is a known class of compounds, many aspects of their action remain unexplained and their new interaction partners are still being discovered. Due to the structural similarity to pyrophosphate, their interaction with pyrophosphate-recognizing enzymes seems to be feasible. In current work, the placental alkaline phosphatase (PLAP) is considered as a potential target for these class of compounds. PLAP is one of the enzymes responsible for degradation of pyrophosphate with high clinical significance. An elevation of PLAP level are considered as a potential cancer marker. An in silico study of complexes formed between selected phosphate derivatives and PLAP was performed. It indicates that all tested compounds: alendronic acid, clodronic acid, etidronic acid, zoledronic acid, imidodiphosphoric acid, pyrophosphoric acid, medronic acid, chloromethylenediphosphonic acid and hypophosphoric acid form a complexes with PLAP, stabilized by hydrogen bonds, hydrophobic and van der Waals interactions. Zoledronic acid, drug used in prevention of bone complications during cancer treatment was found to have the lowest estimated energy of binding (−6.6 kcal/mol). In silico study yielded very low energy of binding also for hypophosphate, equal −6.4 kcal/mol, despite having no identified hydrogen bonds. Subsequent molecular dynamic simulations, followed by molecular mechanics generalized-born surface area with pairwise decomposition calculations confirmed the stability of protein-ligand complexes. The results indicate that selected phosphate derivatives may potentially interact with the enzyme, changing its function, what should be investigated during in vitro studies. Image 1 • Selected bisphosphonate derivatives were docked in placental alkaline phosphatases. • Zoledronic and hypophosphoric acids formed complexes with lowest estimated energies. • Molecular dynamics simulations demonstrated the stability of the complexes. • Among selected drugs, zoledronic acid is suggested to form the most stable complex. • Intestinal and placental alkaline phosphatases exhibit high sequence similarity. [ABSTRACT FROM AUTHOR]

The Rossmann fold enzymes are involved in essential biochemical pathways such as nucleotide and amino acid metabolism. Their functioning relies on interaction with cofactors, small nucleoside-based compounds specifically recognized by a conserved βαβ motif shared by all Rossmann fold proteins. While Rossmann methyltransferases recognize only a single cofactor type, the S-adenosylmethionine, the oxidoreductases, depending on the family, bind nicotinamide (nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate) or flavin-based (flavin adenine dinucleotide) cofactors. In this study, we showed that despite its short length, the βαβ motif unambiguously defines the specificity towards the cofactor. Following this observation, we trained two complementary deep learning models for the prediction of the cofactor specificity based on the sequence and structural features of the βαβ motif. A benchmark on two independent test sets, one containing βαβ motifs bearing no resemblance to those of the training set, and the other comprising 38 experimentally confirmed cases of rational design of the cofactor specificity, revealed the nearly perfect performance of the two methods. The Rossmann-toolbox protocols can be accessed via the webserver at https://lbs.cent.uw.edu.pl/rossmann-toolbox and are available as a Python package at https://github.com/labstructbioinf/rossmann-toolbox. [ABSTRACT FROM AUTHOR]