The significance of halogen bonding in ligand-receptor interactions : the lesson learned from molecular dynamic simulations of the D4D_{4} receptor

Recently, a computational approach combining a structure–activity relationship library containing pairs of halogenated ligands and their corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was developed and used to search for amino acids frequently targeted by halogen bonding, also known as XB hot spots. However, the analysis of ligand–receptor complexes with halogen bonds obtained by molecular docking provides a limited ability to study the role and significance of halogen bonding in biological systems. Thus, a set of molecular dynamics simulations for the dopamine D4 receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand–receptor complex by halogen bonding

Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT6R ligands with noticeable action on AChE/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives

Synteza egozgennych α-aminokwasów zawierających atom krzemu, oparta na niecyklicznych en-karbaminianach.

Poszukiwanie nowych metod syntezy egzogennych aminokwasów jest dynamicznie rozwijającym się kierunkiem badań, ponieważ związki tego typu znajdują zastosowanie w syntezie farmaceutyków. Dodatkowo występowanie w ich strukturze atomu krzemu zamiast atomu węgla może skutkować lepszymi właściwościami biologicznymi oraz bezpieczniejszym profilem toksykologicznym. Celem niniejszej pracy była synteza grupy prekursorów α-aminokwasów zawierających atom krzemu. Kluczowy etap syntezy obejmuje reakcję addycji nukleofilowej do niecyklicznych en-karbaminianów, podczas której następuje spontaniczna migracja grupy tert-butoksylowej z jednoczesnym utworzeniem czwartorzędowego atomu węgla i drugorzędowej grupy aminowej. Grupa oczekiwanych prekursorów aminokwasów z atomem krzemu w strukturze została otrzymana, jednakże nie wszystkie wydajności są satysfakcjonujące i wymagają optymalizacji.W celu otrzymania czystego enancjomerycznie aminokwasu, związek litoorganiczny został wcześniej skompleksowany za pomocą chiralnego ligandu (3-aminopyrolidiny oraz (-)-sparteiny). W ten sposób próbowano uzyskać stereoselektywność w czasie ataku nukloefilowego do wiązania podwójnego. Pomimo tego, nie zaobserwowano stereoselektywności w żadnej z przeprowadzonych prób. Ten mało satysfakcjonujący wynik sugeruje, że proces racemizacji może następować w czasie spontanicznej migracji grupy tert-butoksylowej.Searching for new synthetic routes to non-natural amino acids is a growing field of research, because this kind of compounds may be used in the synthesis of biologically active molecules. Additionally, exchange of carbon by silicon gives huge opportunity to obtain molecules with enhanced biological properties and safe toxicological profile. The aim of this report was to synthesize a group of precursors of original silicon-containing α-amino acids. The key step involves nucleophilic addition on acyclic ene-carbamates generated from the corresponding vinylphoshpates via a palladium catalyzed cross-coupling reaction. During, this nucleophilic addition, spontaneous internal N→C tert-butoxyl group migration is observed, with simultaneous formation of quaternary carbon and secondary amine group. An expected group of precursors of silicon-containing amino acids was obtained. However, not all of the yields are satisfied and need to be improved.To obtain enantiopure precursors of α-amino acids, organolithium compound was first complexed with chiral ligand (3-aminopyrrolidine and (-)-sparteine) in order to achieve stereoselectivity during nucleophilic attack onto the double bond of the acyclic ene-carbamate. However, it appeared that desired stereoselectivity was not observed. This unfortunate result may be a consequence of racemization process which occurs during the spontaneous tert-butoxyl group transfer

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer’s disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer’s disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising