Cyclobutanes in Small-Molecule Drug Candidates

Cyclobutanes are increasingly used in medicinal chemistry in the search for relevant biological properties. Important characteristics of the cyclobutane ring include its unique puckered structure, longer C−C bond lengths, increased C−C π-character and relative chemical inertness for a highly strained carbocycle. This review will focus on contributions of cyclobutane rings in drug candidates to arrive at favorable properties. Cyclobutanes have been employed for improving multiple factors such as preventing cis/trans-isomerization by replacing alkenes, replacing larger cyclic systems, increasing metabolic stability, directing key pharmacophore groups, inducing conformational restriction, reducing planarity, as aryl isostere and filling hydrophobic pockets.     

Relaxation phenomena and structural modifications of substituted polythiophenes during the p-doping processes. An electrochemical and morphological study

Electrodes modified by polythiophenes bearing different substituents have been prepared and the behaviour of the conducting polymers has been studied with respect to the structural phenomena occurring in the correspondence to the doping and the relevant undoping processes. The effects of experimental parameters, such as undoping potential and time, have been investigated. The steric hindrance of the substituents on the polymer chain is demonstrated to play a fundamental role in determining the extent of compactness of the film, as induced by polarisation of the electrode at potentials at which the previously charged polymer is neutralised. Such a conclusion is in accordance with prediction of the electrochemical stimulated conformational relaxation model. Electrochemical AFM measurements have been performed in order to acquire a direct view of the morphological modifications of the polymer coatings during the reduction.     

Dielectric relaxation behaviour of poly(cyclobutyl methacrylate)s

Dielectric behaviour of two poly(methacrylate)s with cyclobutyl groups in the side‐chains has been studied. This investigation was performed by determining the dielectric permittivity and loss in terms of frequency and temperature for poly(cyclobutyl methacrylate) (PCBuM) and poly(cyclobutylmethyl methacrylate) (PCBuMM). Dynamic dielectric measurements show sub‐glass relaxations, probably due to motions in the lateral chain, including the cyclobutyl ring. The effect of the insertion of a flexible spacer group into the side‐chain is also analyzed. The α relaxations were analyzed in terms of the Havriliak–Negami equation and the free volume theory tested according to the Vogel–Fulcher–Tamman–Hesse equation. The conductive and interfacial phenomena were studied by hopping and MacDonald–Coelho models. © 2002 Society of Chemical Industry     

Oligomerization-Dependent Beta-Structure Formation in SARS-CoV-2 Envelope Protein

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. In SARS-CoV-2, the channel-forming envelope (E) protein is almost identical to the E protein in SARS-CoV, and both share an identical α-helical channel-forming domain. Structures for the latter are available in both detergent and lipid membranes. However, models of the extramembrane domains have only been obtained from solution NMR in detergents, and show no β-strands, in contrast to secondary-structure predictions. Herein, we have studied the conformation of purified SARS-CoV-2 E protein in lipid bilayers that mimic the composition of ER–Golgi intermediate compartment (ERGIC) membranes. The full-length E protein at high protein-to-lipid ratios produced a clear shoulder at 1635 cm⁻¹, consistent with the β-structure, but this was absent when the E protein was diluted, which instead showed a band at around 1688 cm⁻¹, usually assigned to β-turns. The results were similar with a mixture of POPC:POPG (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine/3-glycerol) and also when using an E-truncated form (residues 8–65). However, the latter only showed β-structure formation at the highest concentration tested, while having a weaker oligomerization tendency in detergents than in full-length E protein. Therefore, we conclude that E monomer–monomer interaction triggers formation of the β-structure from an undefined structure (possibly β-turns) in at least about 15 residues located at the C-terminal extramembrane domain. Due to its proximity to the channel, this β-structure domain could modulate channel activity or modify membrane structure at the time of virion formation inside the cell.     

Synthesis,characterization and conformational transitions in copolymers of 2‐(o‐chlorophenyl)‐4‐methylene‐1,3‐dioxolane with vinyl monomers

Copolymers of 2‐(o‐chlorophenyl)‐4‐methylene‐1,3‐dioxolane with methyl methacrylate and styrene were synthesized in benzene at 85 °C in the presence of 2,2′‐azobisisobutyronitrile as initiator. The structure of the resulting copolymers was investigated and a polymerization mechanism was proposed. The intrinsic viscosity of the copolymers in dilute solutions of carbon tetrachloride was determined as a function of temperature and conformational transitions were investigated. Copyright © 2004 Society of Chemical Industry     

Structural Versatility of Homo-peptides from Cα,α-dialkylated Glycines

A theoretical and experimental analysis of the preferred conformations of homo-peptides from Cα,α-dialkylated glycines revealed that these compounds are characterised by a marked structural versatility. Fully extended (C₅-conformations). folded (of theβ-bend type), and 3₁₀-helical structures are adopted as a function of side-chain nature. Dimethylated and cyclic side chains favour folded and helical structures, whereas diethylated and longer acyclic side chains favour the fully extended structure. By means of conformational energy calculations the preferred screw sense of the helical structure of homo-peptides from a representative chiral acyclic residue is also anticipated.     

Effects of the excluded volume interactions on the conformational properties of star polymers

The effects of the excluded volume interactions on the conformational properties of star polymers have been studied. First order calculations at the critical dimensionality d = 4 yield the critical exponents of the average quantities up to first order in ε = 4-d. We thus find the partition function, the probability of the end of a branch to reach the central core and the probability of contact of the ends of two branches. The size of the macromolecule, expressed by the mean square radius of gyration 〈s²〉_star is studied in the region where the interactions between the polymeric units repel one another and in the region where the units attract one another. The results are compared with the results of previous works and with experiments.     

Conformational transition of poly(N-vinylpyrrolidone) in aqueous solution of sodium decyl sulphate

The intrinsic viscosity of four poly(N-vinylpyrrolidone) fractions in the molecular weight range from 2.75 × 10⁴ to 3.5 × 10⁵ was measured in a cosolvent mixture of water/sodium decyl sulphate with different sodium decyl sulphate concentrations below its critical micellar concentration. Measurements were made in the temperature range 25?40°C. The value of the a and K parameters of the Mark-Houwink-Sakurada equation were determined. The values obtained for a were in general high, as expected for good solvents. Using the Stockmayer-Fixman equation with the data, K_θ and B, i.e. the short and long range interaction parameters respectively, were calculated, which showed the existence of a conformational change at 12.3 mM sodium decyl sulphate concentration, at all temperatures. The polymer-solvent interaction parameter X for the fraction of molar mass 3.5 × 10⁵ was also determined.     

Evolutionary Algorithms in Drug Design

Designing a drug is the process of finding or creating a molecule which has a specific activity on a biological organism. Drug design is difficult since there are only few molecules that are both effective against a certain disease and exhibit other necessary physiological properties, such as absorption by the body and safety of use. The main problem of drug design is therefore how to explore the chemical space of many possible molecules to find the few suitable ones. Computational methods are increasingly being used for this purpose, among them evolutionary algorithms. This review will focus on the applications of evolutionary algorithms in drug design, in which evolutionary algorithms are used both to create new molecules and to construct methods for predicting the properties of real or yet unexisting molecules. We will also discuss the progress and problems of application of evolutionary algorithms in this field, as well as possible developments and future perspectives.