Zeno Simon

Steric fit in quantitative structure-activity relations

Detailed Contents.- 1 Introduction.- 2 Steric and other Structural Parameters for QSAR.- 2.1 Correlational Equations and Predictor Variables.- 2.2 Steric Parameters.- 2.2.1 Taft Type Steric Parameters: ES, ESc, ESo, ESe and v.- 2.2.2 Amoore Type Steric Parameters.- 2.2.3 Molecular Refractivity and Van der Waals Volume.- 2.2.4 Verloop-Hoogenstraaten-Tipker Steric Parameters.- 2.3 Indicator Variables.- 2.4 Electronic Parameters - Synopsis.- 2.5 Intermolecular Force Parameters.- 3 Topological Indices.- 3.1 Enumeration of Topological Indices.- 3.2 Applications of Topological Indices.- 4 MSD. Minimal Steric Difference (Simple Version).- 4.1 CorrelationsBiological Activity - CMSD.- 4.2 Correlations with MSD and Other Parameters.- 4.2.1 Oxytocic Activity of Oxytocine Aminoacid Replacement Derivatives.- 4.2.2 Carbamates as Acetyl Cholinesterase Inhibitors.- 4.2.3 Schrader-type Organophosphorus Compounds.- 4.2.4 Potential Cytostatic Pt(II)-Diammines.- 4.3 Comparison Between Topological Indices, MSD and Other Sterical Parameters.- 5 MTD-Receptor Site Mapping.- 5.1 Demonstration of formula C5) for ?Y(?t?).- 5.2 QSAR for ?-Chymotrypsine Catalyzed Hydrolyses of Esthers.- 5.2.1 Experimental Data. Orientation of Molecules on the Hypermolecule.- 5.2.2 Optimization Procedure. Mapping of the p2-Site.- 5.2.3 Test of the Optimized Map S*.- 5.2.4 Other QSAR on ?-Chymotrypsine Catalysis.- 5.3 Comparative MTD and Free-Wilson Study of Antiinflamatory Activity of Substituted Cortisol Derivatives.- 5.4 Comparative MTD and Free-Wilson Study of Affinity for ?-Adrenergic Receptors of Epinephrine Substitution Derivatives.- 5.5 Oestrogenic Activity.- 5.6 Dihydrofolate Reductase Inhibition.- 5.7 Other Correlational Work on MTD.- 5.8 Vertices as Indicator Variables.- 6 MCD - Monte Carlo Version for Minimal Steric Difference.- 6.1 The Method to Calculate Nonoverlapping Volumes.- 6.1.1 Description of Molecules.- 6.1.2 Calculation of MCD.- 6.1.3 Computer Implemented MCD - Calculation. The MCD - Program.- 6.1.4 Applications.- 7 Metrics in Biochemistry. The Metric Induced by Minimal Steric Differences.- 8 Conclusions.- 9 Appendix.- 9.1 The MTD/1-program.- 9.2 The MCD - program.- 9.2.1 Succession of Computation Steps in the Program.- 9.2.2 Description of the Subroutines Used.- 9.2.3 Standard Subroutines Used.- 9.2.4 Card Indexes.- 9.2.5 Input Data.- 9.2.6 Structure of Output Data.- 9.2.7 Error Messages.- 10 References.

Charge-transfer spectra of pyrylium iodides

Abstract New methods are described for the preparation of substituted pyrylium halides. Pyrylium iodides have a different colour and an additional charge-transfer absorption band in the crystalline state and in dichloromethane solution as compared with the corresponding perchlorates. The position of the CT band is intermediate between that of tropylium and pyridinium halides. The effect of phenyl groups on the CT band of pyrylium iodides, which is markedly different from the effect on the x-band from the absorption spectrum or on the polarographic half-wave potentials is tentatively explained by the symmetry properties of the lowest empty molecular orbital, thus accounting for the correlation with the y-band from the absorption spectrum.

Preparation and spectra of para-substituted 2,5-diphenyloxazoles

Abstract 2,5 Diaryloxazoles, with the 2-, and 5-aryl groups, substituted in the para position by halo, methyl, methoxy or nitro groups were obtained by the Friedel-Crafts reaction of p-substituted hippuric acid azlactones with benzene, or the hippuric acid azlactone with halobenzenes, toluene, and anisole, followed by treatment with phosphorus oxychloride. Grignard and Ullmann reactions of p-halo-substituted 2,5-diaryloxazoles are described. Absorption spectra of these compounds are discussed and the pronounced bathochromic effect of coupled donor and acceptor groups in both para positions is accounted for by a simple MO treatment.

Steric and other Structural Parameters for QSAR

Remembering that out of 4000–5000 synthesized compounds after screening usually only one proves to be a useful therapeutic agent,the efforts to develop theoretical methods for drug design are easily jus-tifiable,22 The generic term for these methods is Quantitative Structure Activity Relationships — QSAR.

MCD — Monte Carlo Version for Minimal Steric Difference

The previous two chapters described the MSD and MTD techniques for accounting steric effects in receptor-effector interactions. The correlational power of these techniques was illustrated by several examples of QSAR. An analysis of these techniques emphasizes the following features: (i) MTD is a versatile topological method which can be used for series of chemical compounds of largely differing structures. Nevertheless the MTD-techniques, as well as the simple MSD version, becomes ambiguous in some situations, as for example series containing polycyclic molecules or cycles of different sizes: the superposition procedure cannot be exactly defined. (ii) MSD and also MTD use the concept of standard molecule, considered as a complementary copy of the receptor cavity and that of a hypermolecule [implicitly for MSD) which fixes in a convenient way the “topological coordinates” of the molecules in the correlated series. The “best” molecule is used as standard in MSD and the optimization procedure used in MTD starts from it. The use of the term “standard” in this acception may be criticized from the phenomenologic viewpoint. Its use and that of the hypermolecule may be somewhat restrictive in obtaining regressional equations but they are required by the topologic essence of MSD and MTD. (iii) In order to superpose the molecule on the standard, one uses the rule of obtaining minimal nonsuperposable volumes. This rule is not always a sufficient condition, as the superposition “translates” for the MTD formalism also the problem of conformation attacking the receptor. This problem is complex (correct position for bonds to be cleaved, juxtaposition of certain intermolecular bond-forming groups) and requires supplementary informations.

MTD-Receptor Site Mapping

The original idea of minimal steric difference is that affinity towards a receptor decreases linearly with the nonoverlappable volumes of the considered molecule and the receptor14. The point is that the shape of the receptor cavity is not known and also that parts of the molecules stick out into the aqueous environment, being irrelevant for steric fit20. Consider the situation depicted in Figure 9 with a receptor cavity that accommodates exactly a benzenic cycle, and a set of molecules with determined biological activities, A. consisting of phenol(S), cyclohexanone (I), t-butylmethylether(II) and n-hexylethylether(III). According to the MSD-procedure, phenol must be considered as standard(S) and we shall search a maximal superposition of the other molecules upon it. The result of these superpositions is a topological network, the hypermolecule Ĥ, which here has 11 vertices, corresponding to the approximate positions of atomic (nonhydrogen)| nuclei. Cyclohexanone(I) in quasi chair conformation may also enter (almost) perfectly the cavity and occupy vertices 1–7 of H,molecule II — vertices 1, 2, 6, 7, 9, 10, molecule III, vertices 1–5 and 8-11. The corresponding MSD values will be MSDSMSDI=0, MSDII = 5, MSDIII = 4, but it is obvious that groups in the outer space, -OH in S, =0 in I, -OCH3 in II and -0CH2CH3 in III do not interfere with steric fit. The MSD-values “corrected” for unsuperposable atomc on steric irrelevant regions, which we shall term, in what follows, MTD (Minimal Topological Differences) are MTDSMTDI=O, MTDII = 4, MTDIII = 2.

MSD, Minimal Steric Difference (Simple Version)

It is obvious that steric fit depends on the shape of both the biological receptor and the effector molecule. Steric parameters described in the previous chapters rely only on the shape of the effector molecule. The regressional equation will indicate if the receptor prefers large or small values for the corresponding parameter (for example van der Waals volume of the substituent or molecule, width, length, branchedness etc,); at most the optimal value of the shape characteristic corresponding to the steric parameter is indicated.

Metrices in Biochemistry, The Metric Induced by Minimal Steric Differences

Consider a set of objects P = {p, q, r,...}. Function ρ is defined according to relation (1)272,273

Radu Vâlceanu - fondatorul Şcolii Timişorene de Chimie a Compuşilor Elementorganici

\rho {\text{ }}:{\text{ }}P \times P \to R_ +