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Replica exchange molecular dynamics simulations are one of the most popular approaches to enhance conformational sampling of molecular systems. Applications range from protein folding to protein-protein or other host-guest interactions, as well as binding free energy calculations. While these methods are computationally expensive, highly accurate results can be obtained. We recently developed TIGER2hs, an improved version of the temperature intervals with global exchange of replicas (TIGER2) algorithm. This method combines the replica-based enhanced sampling in an explicit solvent with a hybrid solvent energy evaluation. During the exchange attempts, bulk water is replaced by an implicit solvent model, allowing sampling with significantly less replicas than parallel tempering (REMD). This enables accurate enhanced sampling calculations with only a fraction of computational resources compared to REMD. Our latest results highlight several issues with sampling imbalance and parameter sensitivity within the original TIGER2 exchange algorithms that affect the overall state populations. A high sensitivity on replica number and maximum temperature is eliminated by changing to a pairwise exchange kernel (PE) without additional sorting. Simulations are controlled by adjusting the average temperature change per exchange ⟨Δ

The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive

We have investigated the in vitro antimalarial activity of a new series of adenosine derivatives. The results show that N(6)-(1-naphthylmethyl)-5'-deoxy-5'-(amido)adenosines as well as N(6)-(4-phenylbenzyl)-5'-deoxy-5'-(amido)adenosines display significant activity against the malaria-causing parasites, with the sterically demanding bisubstituted species reported being active in most cases in the low-micromolar range. The novel compounds with unusual substitution pattern were obtained applying an efficient convergent polymer-assisted solution-phase (cPASP) synthesis protocol. Thus, we were able to prepare a series of substituted derivatives in parallel that would have been difficult to synthesize by standard techniques. The scope and limitations of the synthetic methodology are discussed.

The synthesis and structure-activity relationship of N(6)-cyclopentyl-3'-substituted-xylofuranosyladenosine analogues with respect to various adenosine receptors were explored in order to identify selective and potent antagonists and inverse agonists for the adenosine A(1) receptor. In particular, the effects of removal of the 5'-OH group and introduction of selected substituents at the 3'-NH(2) position of 9-(3-amino-3-deoxy-beta-D-xylofuranosyl)-N(6)-cyclopentyladenine were probed. A solid phase-assisted synthetic approach was used to optimize the 3'-amide functionality. In view of the general concern of the presence of a 5'-OH moiety with regard to cellular toxicity, the present study describes 5'-deoxy compounds with reasonable affinity for the human adenosine A(1) receptor. Interestingly, this study shows that optimization of the 3'-"up" amide substituent can substantially compensate for the drop in affinity for the adenosine A(1) receptor, which is generally observed upon removal of the 5'-OH group. The fact that for several 3'-amido-substituted (5'-deoxy)-N(6)-cyclopentyladenosine derivatives, guanosine 5'-triphosphate-induced shifts in K(i) values were significantly lower than 1 implies that these analogues behave as inverse agonists. This is further supported by their 1,3-dipropyl-8-cyclopentylxanthine-like capacity to increase forskolin-induced adenosine cyclic 3',5'-phosphate production.

The synthesis of novel quinolino[3,2-d][1]benzazepines and pyrido[3,2-d][1]benzazepines is described. The in vitro antitumor activity of the compounds has been tested in the antitumor screening of the National Cancer Institute (NCI). Several 2,4-diarylpyrido[3, 2-d][1]benzazepin-6-ones and -thiones turned out to exhibit considerable cytotoxicity for tumor cells. For studies of SAR within these series, substituents were introduced into the aromatic rings of the parent systems. Compounds from the thiolactam series tended to show higher potency than the corresponding lactams. Prominent compounds with noteworthy activity and remarkable selectivity for renal cancer cell lines are the lactams 10c, 10g, and 10h and the corresponding thiolactams 11c, 11g, and 11h. Methylation of the azepine nitrogen leads to complete loss of activity, whereas annelation of a triazolo ring at the lactam site or transformation of the thiolactam function to a thiolactim ether results in decreased antitumor activity and selectivity. Consequently, the secondary lactam or thiolactam structure of the seven-membered ring has to be regarded as essential for selective antitumor activity.