BioPrint meets the AI age: development of artificial intelligence-based ADMET models for the drug-discovery platform SAFIRE.

To prioritize compounds with a higher likelihood of success, artificial intelligence models can be used to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of molecules quickly and efficiently. Models were trained with BioPrint database proprietary data along with public datasets to predict various ADMET end points for the SAFIRE platform. SAFIRE models performed at or above 75% accuracy and 0.

Safety screening in early drug discovery: An optimized assay panel.

Background: Several factors contribute to the development failure of novel pharmaceuticals, one of the most important being adverse effects in pre-clinical and clinical studies. Early identification of off-target compound activity can reduce safety-related attrition in development. In vitro profiling of drug candidates against a broad range of targets is an important part of the compound selection process.

Can we discover pharmacological promiscuity early in the drug discovery process?

The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B)>6.

Bovine papillomavirus type 1 DNA replication: the transcriptional activator E2 acts in vitro as a specificity factor.

We previously devised cell-free conditions supporting efficient replication of bovine papillomavirus type 1 (BPV1) DNA (C. Bonne-Andréa, S. Santucci, and P.

Bovine papillomavirus E1 protein binds specifically DNA polymerase alpha but not replication protein A.

Extracts prepared from either mouse cells or monkey cells were examined for the ability to support in vitro bovine papillomavirus type 1 (BPV1) DNA replication, and they were used in parallel as a source of host replication proteins for affinity chromatography. DNA synthesis exhibited an absolute requirement for BPV1 E1 protein. In contrast to previous observations, we found that low levels of E1 were highly efficient in initiating DNA replication in the absence of the BPV1 transcription factor E2.

Tumorigenic transformation of rat FR3T3 fibroblasts carrying an activated myc oncogene requires subsequent mutational events.

Early passage FR3T3 rat cells were co-transfected with a neo resistance gene and pSVc-myc-1, an SV40-driven expression vector carrying an activated murine myc oncogene. Selection in G418 medium produced clones expressing the exogenous myc gene at various levels, with a concomitant loss of expression of the normal c-myc allele. These clones were phenotypically normal, but, in fluctuation tests performed according to Luria and Delbrück (1943) on subcultures independently derived from the same clone, transformed foci appeared as stochastic events with a wide range of fluctuation.

Catabolite modulator factor: physiological properties and in vivo effects.

Catabolite modulator factor (CMF) specifically inhibits the expression of operons sensitive to catabolite repression. Systems known to be catabolite independent are not affected by CMF. The rate of metabolism of CMF depends on the extent of catabolite repression: it is slow under conditions of strong repression and high in catabolically derepressed cells.

Catabolite modulator factor: a possible mediator of catabolite repression in bacteria.

Water soluble extracts of Escherichia coli cells have been found to exert an extremely strong repressive effect upon the expression of catabolite sensitive operons. The compound responsible for this activity has been partially purified and proves to be of low molecular weight and heat stable. The effect of this compound, hereafter designated as catabolite modulator factor, is only partially antagonized by adenosine 3':5'-cyclic monophosphate.