Applications of Multi-Target Computer-Aided Methodologies in Molecular Design of CNS Drugs.

The discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to the discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bioinformatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL. In this review, we analyze the current status of the development of multitarget approaches in quantitative structure-activity relationships (mt-QSAR) for CNS drug discovery; and describes applications of multi-target approaches in molecular modelling (which can be called mt-MM), as well as perspectives for multi-target approaches in bioinformatics in relation to Alzheimer's disease.

On the mechanism of substrate/non-substrate recognition by P-glycoprotein.

P-Glycoprotein (P-gp, multi-drug resistance protein, MDR1) plays a gatekeeper role, interfering delivery of multiple pharmaceuticals to the target tissues and cells. We performed Molecular Dynamics (MD) simulations to generate fifty side-chain variants for P-gp (PDB ID: 4Q9H-L) followed by docking of 31 drugs (0.6≤ER≤22.7) to the whole surface except the ATPase domains and the extracellular part. A selection of the most negative energy complex for each ligand followed. All compounds docked to the two areas - the main binding cavity at the top of P-gp (12.5% of compounds with ER<1; 44.4% of 1≤ER≤2; and 100% of ER>2), and the binding sites in the middle of P-gp (87.5% of ER<1; 55.6% of 1≤ER≤2; and 0% of ER>2). Our results show that anti-substrates (ER<1), intermediate compounds (1≤ER≤2) and strong substrates (ER>2) might behave differently in relation to the P-gp. According to our calculations, the anti-substrates almost do not bind the main binding cavity (MBC) of P-gp and rather approach the other binding sites on the protein; the substrates preferably bind the MBC; the intermediate compounds with 1≤ER≤2 bind both MBC and other binding sites almost equally. The modelling results are in line with the known hypothesis that binding the MBC is prerequisite for the pumping the compound off the P-gp.

Computational Modelling in Studies for Hepatitis C Virus (HCV) NS3 Protease.

Hepatitis C virus (HCV) infected up to 3% of global human population. More than 350 thousand die annually due to liver cirrhosis and hepatocellular carcinoma, developed at the late stages of the disease. The typical ways of HCV transmission are: transfusion of contaminated blood and blood products; sharing syringes among intravenous drug users; use of poorly sterilized medical instruments in certain countries with bad sterilization practice. HCV is hard to identify, at early stages the disease is asymptomatic and progresses slowly. HCV RNA genome is highly variable, and thus interferes developing of a vaccine. HCV NS3 protease has received close attention as the promising drug target. Recent approval of Boceprevir and Telaprevir, the first inhibitors of HCV NS3 protease, has let increase effectiveness of anti-HCV therapy. Though these new medicines show drawbacks in drug resistance and genotype coverage, second and third generation of HCV protease inhibitors will overcome them. Computational modelling had an impact role in these discoveries. Involvement of modelling in studies for Hepatitis C (HCV) NS3 protease is considered in this review.

Risk of defeats in the central nervous system during deep space missions.

Space flight factors (SFF) significantly affect the operating activity of astronauts during deep space missions. Gravitational overloads, hypo-magnetic field and ionizing radiation are the main SFF that perturb the normal activity of the central nervous system (CNS). Acute and chronic CNS risks include alterations in cognitive abilities, reduction of motor functions and behavioural changes. Multiple experimental works have been devoted to the SFF effects on integrative functional activity of the brain; however, the model parameters utilized have not always been ideal and consistent. Even less is known regarding the combined effects of these SFF in a real interplanetary mission, for example to Mars. Our review aims to systemize and analyse the last advancements in astrobiology, with a focus on the combined effects of SFF; as well as to discuss on unification of the parameters for ground-based models of deep space missions.

Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: In silico ligand screening and molecular dynamics studies of inhibition.

The allosteric pocket of the Dengue virus (DENV2) NS2B/NS3 protease, which is proximal to its catalytic triad, represents a promising drug target (Othman et al., 2008). We have explored this binding site through large-scale virtual screening and molecular dynamics simulations followed by calculations of binding free energy. We propose two mechanisms for enzyme inhibition. A ligand may either destabilize electronic density or create steric effects relating to the catalytic triad residues NS3-HIS51, NS3-ASP75, and NS3-SER135. A ligand may also disrupt movement of the C-terminal of NS2B required for inter-conversion between the "open" and "closed" conformations. We found that chalcone and adenosine derivatives had the top potential for drug discovery hits, acting through both inhibitory mechanisms. Studying the molecular mechanisms of these compounds might be helpful in further investigations of the allosteric pocket and its potential for drug discovery.