Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX.

In this work, we present DrugSolver CavitomiX, a novel computational pipeline for drug repurposing and identifying ligands and inhibitors of target enzymes. The pipeline is based on cavity point clouds representing physico-chemical properties of the cavity induced solely by the protein. To test the pipeline's ability to identify inhibitors, we chose enzymes essential for SARS-CoV-2 replication as a test system. The active-site cavities of the viral enzymes main protease (Mpro) and papain-like protease (Plpro), as well as of the human transmembrane serine protease 2 (TMPRSS2), were selected as target cavities. Using active-site point-cloud comparisons, it was possible to identify two compounds-flufenamic acid and fusidic acid-which show strong inhibition of viral replication. The complexes from which fusidic acid and flufenamic acid were derived would not have been identified using classical sequence- and structure-based methods as they show very little structural (TM-score: 0.1 and 0.09, respectively) and very low sequence (~ 5%) identity to Mpro and TMPRSS2, respectively. Furthermore, a cavity-based off-target screening was performed using acetylcholinesterase (AChE) as an example. Using cavity comparisons, the human carboxylesterase was successfully identified, which is a described off-target for AChE inhibitors.

A nontoxic pain killer designed by modeling of pathological receptor conformations.

Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral µ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.

[Medicine from the computer]. / Medizin aus dem Computer.

Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

[Medicine from the computer]. / Medizin aus dem Computer.

Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

[Medicine from the computer]. / Medizin aus dem Computer.

Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.

Effect of plunger diameter on the push-out bond values of different root filling materials.

AIMS: To evaluate the effect of plunger diameter on the push-out bond strength of different root filling materials to root canal dentine. METHODOLOGY: Freshly extracted human incisors (n=90) were decoronated, and the root canals were enlarged with post drills. Prepared roots were placed into a custom alignment apparatus to embed the roots vertically within self-curing acrylic resin. The specimens were randomly assigned into three groups according to the root filling system used: gutta-percha/AH Plus; Resilon/Epiphany; and fibre-reinforced composite (FRC)/Duolink resin cement. After filling, the specimens were further subdivided according to the diameter of the plunger used to employ the debonding force: 0.75, 1 and 1.25 mm. Intra-radicular bond strength was measured using the push-out test at a cross-head speed of 1 mm min(-1) . The data were analysed statistically using Kruskal-Wallis test with Bonferroni correction at P = 0.05. RESULTS: Regardless of the plunger diameter, FRC yielded the highest bond strength, followed by gutta-percha and Resilon, respectively (P<0.001). In all groups, greater plunger diameter resulted in an apparent increased bond strength, but the differences were only significant in the FRC group, with the 1.25-mm plunger generating higher debonding values compared with that of its 0.75- and 1-mm versions (P<0.001). In the gutta-percha and Resilon groups, the majority of specimens had adhesive failures. Roots filled with FRC exhibited more cohesive failures than those of the other test groups. CONCLUSIONS: Different plunger diameters are associated with significantly different intra-radicular push-out bond strengths of root filling systems.

Evaluation of the apical leakage of isobutyl cyanoacrylate when used as a root canal sealant.

The sealing properties of isobutyl cyanoacrylate were evaluated in extracted single-rooted human teeth. In the experimental group, instrumented root canals were obturated with isobutyl cyanoacrylate and gutta-percha by using the lateral condensation technique. In the control group instrumented root canals were obturated with gutta-percha only. The penetration of radioactive 131I was evaluated by an autoradiographic technique. No leakage was observed in the experimental group. This study shows that isobutyl cyanoacrylate is a good apical sealant.