The Path Towards a Tailored Clinical Biosimilar Development.

Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity.

The N6-methyl group of adenine further increases the BI stability of DNA compared to C5-methyl groups.

Methylated DNA bases are natural modifications which play an important role in protein-DNA interactions. Recent experimental and theoretical results have shown an influence of the base modification on the conformational behavior of the DNA backbone. MD simulations of four different B-DNA dodecamers (d(GC)(6), d(AT)(6), d(G(5mCG)(5)C), and d(A(T6mA)(5)T)) have been performed with the aim to examine the influence of methyl groups on the B-DNA backbone behavior.

M.TaqI facilitates the base flipping via an unusual DNA backbone conformation.

MD simulations have been carried out to understand the dynamical behavior of the DNA substrate of the Thermus aquaticus DNA methyltransferase (M.TaqI) in the methylation process at N6 of adenine. As starting structures, an x-ray structure of M.

Towards an understanding of DNA recognition by the methyl-CpG binding domain 1.

CpG methylation determines a variety of biological functions of DNA. The methylation signal is interpreted by proteins containing a methyl-CpG binding domain (MBDs). Based on the NMR structure of MBD1 complexed with methylated DNA we analysed the recognition mode by means of molecular dynamics simulations.

Z-DNA's conformer substates revealed by FT-IR difference spectroscopy of nonoriented left-handed double helical poly(dG-dC).

Nonoriented hydrated films of double helical poly(dG-dC) in the Z-form were studied by Fourier transform infrared (FT-IR) spectroscopy either as equilibrated slow-cooled samples between 290 and 220 K or, after quenching into the glassy state, as nonequilibrated film isothermally at 200, 220, and 240 K. IR spectral changes on isothermal relaxation at 200 and 220 K toward equilibrium, caused by interconversion of two conformer substates (CS) called Z1 and Z2, are revealed by IR difference spectra. Pronounced spectral changes on Z1-to-Z2 interconversion occur between approximately 750-1250 cm(-1) and these are attributed to structural changes of the phosphodiester-sugar backbone caused by changes of torsion angles, and to decreasing hydrogen-bonding of the ionic phosphate group with water molecules.

Cooperative effects on the formation of intercalation sites.

Daunomycin is one of the most important agents used in anticancer chemotherapy. It interacts with DNA through intercalation of its planar chromophore between successive base pairs. The effect of intercalation on structure, dynamics and energetics is the topic of a wealth of scientific studies.

Water-mediated contacts in the trp-repressor operator complex recognition process.

Water-mediated contacts are known as an important recognition tool in trp-repressor operator systems. One of these contacts involves two conserved base pairs (G(6).C(-6) and A(5).

Daunomycin intercalation stabilizes distinct backbone conformations of DNA.

Daunomycin is a widely used antibiotic of the anthracycline family. In the present study we reveal the structural properties and important intercalator-DNA interactions by means of molecular dynamics. As most of the X-ray structures of DNA-daunomycin intercalated complexes are short hexamers or octamers of DNA with two drug molecules per doublehelix we calculated a self complementary 14-mer oligodeoxyribonucleotide duplex d(CGCGCGATCGCGCG)2 in the B-form with two putative intercalation sites at the 5'-CGA-3' step on both strands.

C5-methylation of cytosine in B-DNA thermodynamically and kinetically stabilizes BI.

We have examined the backbone dynamics of two alternating purine-pyrimidine dodecamers. One sequence consists of "pure" GC bases; the other one contains 5-methylcytosines. The effect of the methyl groups on the backbone substates BI/BII was investigated by means of molecular dynamics.

Hydration of hydroxypyrrole influences binding of ImHpPyPy-beta-Dp polyamide to DNA.

Ligands which are able to recognize DNA sequence specifically are of fundamental interest as transcription controlling drugs. Recently a polyamide ligand was developed (ImHpPyPy-beta-Dp) which differentiates in a dimeric arrangement between all four possible base pair steps in the minor groove. This is a landmark for the design of DNA binding drugs because it was believed that such a recognition could only be possible in the major groove of DNA.

PvuII-endonuclease induces structural alterations at the scissile phosphate group of its cognate DNA.

We investigated the PvuII endonuclease with its cognate DNA by means of molecular dynamics simulations. Comparing the complexed DNA with a reference simulation of free DNA, we saw structural changes at the scissile phosphodiester bond. At this GpC step, the enzyme induces the highest twist and axial rise, inclination is increased and the minor groove widened.