Quantitative Structure–Activity Relationship of the 4,5α‐Dihydrotestosterone Steroid Family

Abstract

Predictive Quantitative Structure -Activity Relationship (QSAR) models of Anabolic/ Androgenic (A/A) activities for the 4,5a-dihydrotestosterone steroid family were obtained by means of multilinear regression using quantum and physicochemical Molecular Descriptors (MDs) as well as a genetic algorithm for the selection of the best subset of MDs. MDs included in our QSAR models allow the structural interpretation of the biological process, evidencing the main role of the shape of molecules, hydrophobicity, and electronic properties. Attempts were made to include lipophilicity (octanol -water partition coefficient) as well as electronic (lowest unoccupied molecular orbital properties and dipole moment) values of the whole molecules in the multivariate relations. It was found from the study that the calculated net charges by semiempirical methods of different atoms in the steroid nucleus [atoms 4 (ring A), 8 (bridgeheads of rings B and C), 11 (ring C) 13 (fusion points of rings C and D), and 16 (ring D)] contribute significantly to binding affinity. The found MDs can also be efficiently used in similarity studies based on cluster analysis. Our model for the A/A ratio (expressed by the weights of the levator ani muscle/ventral prostate in mice) predicts that 2a, 3a-difluoro-methylene-17a-methyl-5a-androstan-17b-ol (13) is the most potent anabolic steroid. By contrast, the 17a-methyl-2b, 17b-dihydroxy-5a-androstane (16) is flagged as the least potent anabolic steroid. The approach described in this report is an alternative for the discovery and optimization of leading anabolic compounds among steroids and analogues. It also gives an important role to electron exchange terms of molecular interactions to this kind of steroid activity.

Applying pattern recognition methods plus quantum and physico‐chemical molecular descriptors to analyze the anabolic activity of structurally diverse steroids

“…They define the ability of the drug to join to the receptor. 25,26 The electronic descriptors calculated by quantum mechanical procedures were: hydration energy (E H 2 O ), 31 polarizability (P), 32 electric dipole moment (), heat of formation (HF), electronic energy (EE), total energy (E T ), HOMO (highest occupied molecular orbital) energy, LUMO (lowest unoccupied molecular orbital) energy, net atomic charges (q) of C atoms 1-17 in the steroid backbone (q 1 -q 19 ), 33 electrophilicity index (! ), chemical potential (U), chemical hardness (), and chemical softness (S).…”

“…The dataset of steroids, studied more extensively with different methods by several research groups, is the steroid benchmark with the corresponding globulin affinity. [15][16][17] Recently, we reported QSAR models for congeneric series of AASs: 17-hydroxy-5-androstane, 18 4,5-dihydrotestosterone 19 and testosterone 20 steroid families.…”

Anabolic and androgenic activities of 19-nor-testosterone steroids: QSAR study using quantum and physicochemical molecular descriptors

“…A complete discussion of the clustering is out of the context of the present study, but several interesting features should be noted. The compounds: [1][2][3][4], [6][7][8][9][10][11][12][13][14] and [19][20][21][22][23][24][25] are 19-nor-steroids with a carbonyl group (-C O) in the atom 3 and a vinyl group (-C C-) in the atoms 4 and 5 (Fig. 2).…”

“…The steroid benchmark with the corresponding globulin affinity is the most extensively studied dataset of steroids [14][15][16][17][18]. Recently, we reported multi-linear regression (MLR) QSAR models for congeneric series of AAS: 17␤-hydroxy-5␣-androstane [19], 4,5␣-dihydrotestosterone [20] and testosterone [21] steroid families. We reported too a robust biosilico model of linear discriminant analysis (LDA) [22].…”

Disclosure the Relationship ”Structure Biology Activity” on the Basis of Conformational Analysis of the Brassinosteroid’s Stereoisomers by the Molecular Modeling Methods

“…Из данных таблицы следует, что небольшие различия химического строения боковой цепи в исследуемых БС приводят к значительным изменениям ее структуры и конформационных возможностей при переходе из кристаллического состояния в газовую фазу. 4), наблюдаются незначительные изменения структуры боковой цепи по сравнению с кристаллическим состоянием. Основные структурные изменения в семействе низкоэнергетических конформеров RRSi молекулы (1) происходят в концевой части боковой цепи (ориентация заместителей относительно связи С24-С25).…”