Drug-receptor geometry {drug structure} is a physico-chemical property and can be quantitative.
structure-activity relationships
Drugs have structure-activity relationships (SAR), which can be quantitative (QSAR). Drugs have property-activity relationships.
activity
Drug activity equals physicochemical-variable function. Drug activity relates to concentration, partition coefficient, or product formation. Stages have probabilities. Drug activity is proportional to concentration product, complexing probability, changing probability, and partitioning probability.
activity: complex formation
Drugs form complexes with receptors {intrinsic activity, complex}. Drugs {chemotherapeutic drug} can cause chemical reactions or conformational changes. Drugs {pharmacodynamic drug, complexes} can make complexes but do not change conformation or cause reactions.
Complex-formation probability is formation-reaction equilibrium constant. Equilibrium constant depends on both equilibrium type and substituent electronic influence on reaction center. log(K) = k1 * sigma + k2 {linear free energy equation, structure} (LFE). log(1 / concentration) = k1 * sigma + k2. Electronic influences are universal and have tables of values. Equilibrium type results from multiple regression analysis of simultaneous equations.
activity: partitioning
If hydrophobicity affects drug structure, partition coefficient affects activity. log(K) = k3 * pi + k1 * sigma + k2 and log(1 / concentration) = k3 * pi + k1 * sigma + k2. Partition coefficients are universal and have tables of values.
activity: transport
Drugs have to get to target site. Drug transport involves diffusion, active transport, adsorption, binding to serum proteins, or membrane interactions. Mechanisms that oppose drug transport are excretion, metabolism, and localization in fat. Excretion is faster for hydrophilic. Metabolism is faster for hydrophobic. Localization in fat is faster for hydrophobic. Drug transport affects drug activity. log(K) = k3 * pi + k1 * sigma + k2 - k4 * pi^2. log(1 / concentration) = k3 * pi + k1 * sigma + k2 - k4 * pi^2. Drug transport factors are universal and have tables of values.
structure
Molecule structure depends on atom types, atom numbers, chemical bonds, spatial relations, and atom locations. Features are either present or absent, with no interactions.
structure: molecular connectivity indices
Kier and Hall used features such as electrotopologic state index, valence, molecular shape and flexibility {kappa index, structure}, branching, unsaturation, cyclization, and heteroatom position. They found molecular connectivity indices, based on Randic's branching index, calculated from hydrogen-suppressed chemical graph or skeleton structure. For example, atoms can have number of sigma electrons contributed {simple delta index, structure} or number of valence electrons {valence delta}.
structure: molecular orbital
Quantum-mechanical structure description uses molecular orbital (MO) theory. Molecular orbitals depend on electron location and energy. Total conformation energy gives probability. MO typically ignores solvents.
Highest occupied molecular orbital gives the most-reactive electron for electron-rich nucleophilic molecules. Lowest unoccupied molecular orbital gives the most-reactive electron for electron-poor electrophilic molecules.
MO can test reaction paths and find thermodynamic information, by checking energies in different configurations.
Molecular orbitals can be linear combinations of atomic orbitals (LCAO). Atomic-orbital contribution probability is linear-coefficient squared, and point charge is probability sum.
structure: interactions
Comparative Molecular Field Analysis (CoMFA) uses partial least-squares to analyze grid around site atom and find grid-point hydrophobic, electrostatic, and steric interactions.
structure: ab initio
Ab initio analysis uses electron locations to find charges, electrostatic potentials, dipole moments, ionization energies, electron affinity, and activation energies. Semiempiric analysis uses only valence electrons and parameterizes core electrons. Modified neglect of differential overlap (MNDO) ignores overlaps. Perturbative configuration interaction using localized orbitals (PCILO) uses perturbations. Varying bond angles, bond lengths, and torsion angles can find minimum energy and preferred conformation.
structure: axial-equatorial configuration
Non-conjugated-ring substituent positions can be in ring plane {equatorial configuration} or perpendicular {axial configuration}.
structure: branching
Carbon chain can have fork {branching}.
structure: ionization degree
Molecule can have charge {degree of ionization} {ionization degree}.
structure: dipole moment
Opposite charges can separate by distance.
structure: electrostatic potential
Electric potential energy comes from electric field.
structure: molecular similarity
Molecules can be similar in 3D atomic configuration, atom pairs, chemical graphs, electron densities, field potentials, molecular fragments, molecular properties, molecular surfaces, steric volumes, or topological/information theory indexes.
structure: orientation
Molecule spatial alignment is at receptor site.
structure: radical
Atoms can have one electron in outer orbital.
structure: singlet or triplet state
Orbital state can have paired electrons {singlet state}. Orbital state can have unpaired electrons {triplet state}.
Connection tables number non-hydrogen atoms, name atomic elements, name atom number to which they connect, and name atom types {Chemical Abstracts Service} (CAS).
Molecules can be vectors, including chemical activity, in abstract space {Chemical Descriptor Space} (CDS).
Base compounds {building block} can attach one to four small molecules {combinatorial chemistry} to add functional groups and make compound libraries with molecular weights 300 to 750.
Tables {connection table} can describe three-dimensional structures.
Matrices {connectivity matrix} can graph molecular connections.
Electrostatic fields make potentials {Coulombic potential}.
Polar solute can cross lipid membrane if hydrogen bonds to water break {desolvation}. Polar solute with fewer hydrogen bonds to water and lower hydrogen-bonding potentials can diffuse more easily.
Indexes {electrotopologic state index} can depend on topology structures.
Molecular markers {encoding tag} can track combinatorial-chemistry molecules.
Molecule atoms {hetero} can be not carbon C or hydrogen H. Hetero can refer to solvent, non-solvent, water, ion, or ligand atoms.
Compounds {heterocyclic compound} can have rings with atoms other than carbon.
Molecular regions can repel water {hydrophobicity}.
Cytochrome P450 has types {isoform}.
Combinatorial chemistry makes compound permutations {library of compounds}.
Tables {nearest neighbor table} can rank different compounds by similarity.
Superimposed molecules show constants across diverse molecules and so identify sites and reactions {pharmacophore}.
Molecules have atomic properties, functional groups, and molecular properties {similarity matrix}.
Oxygen can have positive charge {superoxide anion}.
Possible compound permutations can be in database {virtual compound library}.
Strings {Wiswesser line notation} (WLN) can uniquely describe three-dimensional structure.
X-ray crystallography patterns {X-ray structure} can indicate atom positions.
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Date Modified: 2022.0225