Classification (Agonist/Antagonist) and Regression "Structure-Activity" Models of Drug Interaction with 5-HT6.

Introduction: One promising target for novel psychotropic drugs is the 5-HT6 receptor, GProtein- Coupled Receptor (GPCR) family, displaying seven transmembrane domains. There is considerable interest in how both 5-HT6 receptor agonist and antagonist compounds can have marked procognitive effects.

Methods: An exact structure of the 5-HT6 receptor is not available, so application of powerful methods of (Q)SAR and molecular modelling, which play an essential role in modern drug design, are currently limited to structure-based homology models.

Aqueous Drug Solubility: What Do We Measure, Calculate and QSPR Predict?

Detailed critical analysis of publications devoted to QSPR of aqueous solubility is presented in the review with discussion of four types of aqueous solubility (three different thermodynamic solubilities with unknown solute structure, intrinsic solubility, solubility in physiological media at pH=7.4 and kinetic solubility), variety of molecular descriptors (from topological to quantum chemical), traditional statistical and machine learning methods as well as original QSPR models.

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.

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.

CNS Multiparameter Optimization Approach: Is it in Accordance with Occam's Razor Principle?

A detailed analysis of the possibility of using the Multiparameter Optimization approach (MPO) for CNS/non-CNS classification of drugs was carried out. This work has shown that MPO descriptors are able to describe only part of chemical transport in the CNS connected with transmembrane diffusion. Hence the "intuitive" CNS MPO approach with arbitrary selection of descriptors and calculations of score functions, search of thresholds of classification, and absence of any chemometric procedures, leads to rather modest accuracy of CNS/non-CNS classification models.

Physicochemical property profile for brain permeability: comparative study by different approaches.

A comparative study of classification models of brain penetration by different approaches was carried out on a training set of 1000 chemicals and drugs, and an external test set of 100 drugs. Ten approaches were applied in this work: seven medicinal chemistry approaches (including "rule of 5" and multiparameter optimization) and also three SAR techniques: logistic regression (LR), random forest (RF) and support vector machine (SVM). Forty-one different medicinal chemistry descriptors representing diverse physicochemical properties were used in this work.

In silico Prediction of Aqueous Solubility: a Comparative Study of Local and Global Predictive Models.

32 Quantitative Structure-Property Relationship (QSPR) models were constructed for prediction of aqueous intrinsic solubility of liquid and crystalline chemicals. Data sets contained 1022 liquid and 2615 crystalline compounds. Multiple Linear Regression (MLR), Support Vector Machine (SVM) and Random Forest (RF) methods were used to construct global models, and k-nearest neighbour (kNN), Arithmetic Mean Property (AMP) and Local Regression Property (LoReP) were used to construct local models.

Calculation of aqueous solubility of crystalline un-ionized organic chemicals and drugs based on structural similarity and physicochemical descriptors.

Solubilities of crystalline organic compounds calculated according to AMP (arithmetic mean property) and LoReP (local one-parameter regression) models based on structural and physicochemical similarities are presented. We used data on water solubility of 2615 compounds in un-ionized form measured at 25±5 °C. The calculation results were compared with the equation based on the experimental data for lipophilicity and melting point.

Thermodynamic aspects of solubility process of some sulfonamides.

The thermodynamic aspects of solubility process of sulfonamides with the general structures C(6)H(5)-SO(2)NH-C(6)H(4)-R (R=4-NO(2); 4-Cl) and 4-NH(2)-C(6)H(4)-SO(2)NH-C(6)H(4)-R (R=4-NO(2); 4-CN; 4-Cl; 4-OMe; 4-C(2)H(5)) in water, phosphate buffer with pH 7.4 and n-octanol (as phases modeling various drug delivery pathways) were studied using the isothermal saturated method.

Thermodynamic and structural aspects of sulfonamide crystals and solutions.

The crystal structures of three sulfonamides with the general structure 4-NH(2)-C(6)H(4)-SO(2)NH-C(6)H(4/3)-R (R = 4-Et; 4-OMe; 5-Cl-2-Me) have been determined by X-ray diffraction. On the basis of our previous data and the results obtained a comparative analysis of crystal properties was performed: molecular conformational states, packing architecture, and hydrogen bond networks using graph set notations. The thermodynamic aspects of the sulfonamide sublimation process have been studied by investigating the temperature dependence of vapor pressure using the transpiration method.

Sulfonamides as a subject to study molecular interactions in crystals and solutions: sublimation, solubility, solvation, distribution and crystal structure.

Crystal structures of 4-amino-N-(4-chlorophenyl)-benzene-sulfonamide (IV), 4-amino-N-(2,3-dichlorophenyl)-benzene-sulfonamide (V), 4-amino-N-(3,4-dichlorophenyl)-benzene-sulfonamide (VI) and 4-amino-N-(2,5-dichlorophenyl)-benzene-sulfonamide (VII) were solved by X-ray diffraction method. Temperature dependencies of saturated vapour pressure and thermodynamic functions of sublimation process were calculated (IV: delta Gsub298=74.0 kJ mol(-1), delta Hsub298=134.

Studying thermodynamic aspects of sublimation, solubility and solvation processes and crystal structure analysis of some sulfonamides.

Crystal structures of N-(2-chlorophenyl)-benzene-sulfonamide (I), N-(2,3-dichlorophenyl)-benzene-sulfonamide (II), N-(4-chlorophenyl)-benzene-sulfonamide (III) were solved by X-ray diffraction method. Temperature dependencies of saturated vapor pressure and thermodynamic functions of sublimation process were calculated (I: DeltaG(sub)(298)=50.4kJmol(-1); DeltaH(sub)(298)=114+/-1kJmol(-1); DeltaS(sub)(298)=213+/-3Jmol(-1)K(-1); II: DeltaG(sub)(298)=54.

Physicochemical descriptors in property-based drug design.

The contribution of physicochemical descriptors to lipophilicity, water solubility, and intestinal absorption and oral bioavailability in humans is considered. Partitioning in the octanol/water system is presented as a competition between two opposing effects: volume and hydrogen bond acceptor ability. Water solubilities of liquid compounds are roughly equal to their reciprocal logP values.

3D hydrogen bond thermodynamics (HYBOT) potentials in molecular modelling.

A new approach is proposed to more accurately estimate the energies of H-bond interactions in three-dimensional (3D) molecular modelling. The approach is based on the use of H-bond acceptor and donor enthalpy factor values calculated by means of program HYBOT, the use of a sigmoid relationship to determine the optimum H-bond distances and established force-field methods to determine distance and angle dependencies. The base-pair interactions in a short A-form RNA double-helix are presented as an example of enthalpy calculations of hydrogen bonding for a model system.

SLIPPER-2001 -- software for predicting molecular properties on the basis of physicochemical descriptors and structural similarity.

A new approach for predicting the lipophilicity (log P), solubility (log Sw), and oral absorption of drugs in humans (FA) is described. It is based on structural and physicochemical similarity and is realized in the software program SLIPPER-2001. Calculated and experimental values of log P, log Sw, and FA for 42 drugs were used to demonstrate the predictive power of the program.

Conformation of 18-Crown-5 and Its Influence on Complexation with Alkali and Ammonium Cations: Why 18-Crown-5 Binds More Than 1000 Times Weaker Than 18C6.

Stability constants of potassium, sodium, and benzylammonium salts with 18C5 are determined in water, methanol, and acetonitrile by potentiometric titrations. The corresponding free energies DeltaG agree within the error with those obtained from calorimetric titrations. In comparison to 18C6 the DeltaG values are lower by 14 to 16 kJ/mol, with methanol or acetonitrile as solvent and K(+) or benzylammonium salts.