Dmitry S. Karlov

Synthesis and properties of diadamantyl-containing symmetric diureas as target-oriented inhibitors of human soluble epoxide hydrolase

A series of target-oriented competitive inhibitors of human soluble epoxide hydrolase have been synthesized. The compounds retain the inhibitory properties at concentrations down to 4 nM. Based on the results of molecular modeling, it has been shown that the high inhibitory activity of this series of compounds is achieved by a unique mode of the binding to the active site of the enzyme.

Adamantyl thioureas as soluble epoxide hydrolase inhibitors

A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.

Pharmacophore analysis of positive allosteric modulators of AMPA receptors

A 3D QSAR study of a set of positive allosteric modulators of AMPA receptors was performed using the CoMFA approach. It was shown that the van der Waals component introduces the major contribution to the predicted pEC50 values, while the contribution of the electrostatic component is minor. The pharmacophore hypothesis for positive allosteric modulators was generated and validated.

Computer-aided modeling of activity and selectivity of quinazolinones as noncompetitive NMDA receptor antagonists

NMethylDaspartic acid (NMDA) receptor, belonging to the group of glutamate ionotropic recep� tors, is a very important biological target. It is involved in many significant neurophysiological processes in the central nervous system associated with the transfer of fast synaptic excitation, formation of memory, etc. Hyperactivation of NMDA receptor leads to a number of pathological conditions, including various neuro� degenerative diseases. For this reason, its antagonists and blockers were shown to be effective as neuropro� tectors, in particular, in treatment of Alzheimers dis� ease. In terms of architecture, NMDA receptor has a heterotetrameric structure. Usually it consists of two glycinebinding subunits GluN1 and two glutamate� binding subunits GluN2. The neurophysiological pro� file of a compound is determined primarily by the selectivity for different GluN2 subtypes, which are located predominantly in different brain structures. In particular, selective antagonists of GluN2D are of considerable interest for the treatment of Parkinsons disease (1). The purpose of this work was to study the rela� tionships of the structure with activity and selectiv� ity for four subtypes of the GluN2 subunit (GluN2A, GluN2B, GluN2C, and GluN2D) in a series of quinazolin�4�one derivatives, noncompet� itive antagonists of the receptor. Within the frame� work of the method used in the study—molecular field topology analysis (MFTA) (2-4)—a model of bioactivity is constructed on the basis of consider� ation of values of local molecular descriptors (prop� erties of atoms and bonds) in related structures and analysis of their effect on activity. A common frame of reference for a meaningful comparison of such local properties is provided by a molecular super� graph, which is constructed by topological superpo� sition of twodimensional structures of compounds (structural formulas) of a training set and allows each structure in the training set to be superim� posed. In addition to the predictive model, which is based on partial least squares regression and corre� lates these properties in all positions of the molecu� lar supergraph with bioactivity, this method makes it possible to obtain a graphic map of their influence on activity.

On mechanism of allosteric modulation of NMDA receptor via amino-terminal domains

A possible mechanism of action of the allosteric modulators of NMDA (N-methyl-d-aspartate) receptors is proposed that involves the stabilization of the twisted closed-clamshell configuration of the amino-terminal domains of GluN1 and GluN2B subunits by negative modulators while positive modulators stabilize a roughly parallel tight arrangement of these domains. These respective motions may play an important role in the transition between the open-channel and closed-channel states of the receptor. In addition, some features of the negative modulator binding site found by means of the molecular dynamics study and pocket analysis can be used in the rational design of the allosteric NMDA receptor modulators.

Computer-aided design of negative allosteric modulators of NMDA receptor

22 The N methyl D aspartic acid (NMDA) receptor, along with kainic acid and amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid (AMPA) receptors, belongs to the large family of glutamate gated ion channels involved in many important neurophysiolog ical processes in the central nervous system associated with fast synaptic excitation transmission, memory formation, etc. [1]. Hyperactivation of NMDA recep tor causes a number of pathological conditions, including various neurodegenerative diseases. For this reason, its antagonists and reversible ion channel blockers were shown to be effective neuroprotector agents, in particular, for the treatment of Alzheimer’s disease [2].

MM-GBSA and MM-PBSA performance in activity evaluation of AMPA receptor positive allosteric modulators

MM-GBSA and MM-PBSA performance in activity evaluation of AMPA receptor positive allosteric modulators Dmitry S. Karlov , Mstislav I. Lavrov, Vladimir A. Palyulin* and Nikolay S. Zefirov Department of Chemistry, Lomonosov Moscow State University, 1 Build. 3, Leninskie Gory, Moscow, 119991 Russian Federation; Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severny proezd, Chernogolovka, Moscow Region 142432, Russian Federation

Molecular design of proneurogenic and neuroprotective compounds—allosteric NMDA receptor modulators

N-Methyl-D-aspartic acid (NMDA) receptor is a promising target for treatment of neurodegenerative diseases and other brain disorders as well as for designing proneurogenic compounds able to stimulate neurogenesis in adult brain. We analyzed the structure of the binding site of negative allosteric modulators in the amino-terminal domain of the NMDA receptor and identified possible modes of their binding as well as performed molecular design of new modulators that significantly differ from the known ones in structure and binding mode. In addition, we formed a focused library of chemical compounds with potential neuroprotective and proneurogenic properties, desirable set of pharmacokinetic properties, and low toxicity, which can be the basis for development of new-generation drugs.

Molecular modeling of the transmembrane domain of mGluR2 metabotropic glutamate receptor and the binding site of its positive allosteric modulators.

13 Glutamic acid is a key excitatory neurotransmitter in the mammalian central nervous system, which can act by two main mechanisms associated with two groups of membrane receptors. Fast synaptic trans mission is mediated by the glutamate dependent cat ion channels (ionotropic glutamate receptors), whereas the metabotropic glutamate receptors (mGluR), belonging to the class of G protein coupled receptors (GPCRs), are responsible for a “slow” neu romodulation through the regulation of intracellular metabolic processes [1]. These receptors contain a large extracellular N terminal VFT domain, where the endogenous agonist, glutamate, is bound. Glutamate induced conformational changes are transmitted through the cysteine rich domain (CRD) and then through the transmembrane 7TM domain, formed by seven α helices, to the intracellular C terminal domain, thereby activating the second messenger sig naling pathways.