Rational approaches of drug design for the development of selective estrogen receptor modulators (SERMs), implicated in breast cancer

• Published in: Bioorganic chemistry 2020-01, Vol.94, p.103380, Article 103380
• Main Authors: Makar, Subhajit, Saha, Tanmay, Swetha, Rayala, Gutti, Gopichand, Kumar, Ashok, Singh, Sushil K.
• Format: Article
• Language: English
• Subjects: 17-β Estradiol and His524; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Dose-Response Relationship, Drug; Drug Design; Estrogen receptor; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - agonists; Estrogen Receptor beta - antagonists & inhibitors; Estrogen Receptor beta - metabolism; Female; Helix-12; Humans; Ligand Binding Domain (LBD); Molecular Structure; Pharmacophore; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; SERMs; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103380

[Display omitted] •OH group produced a hydrogen bond with His 475 of ERβ, was equivalent to 524 in ERα.•The pharmacophores of ERs consists of two hydroxyl groups, are 11 Aͦ apart.•Val392 in ERα is replaced by Met344 in ERβ in plane of bounded estradiol in B-ring pocket.•2-Arylindole derivatives showed tremendous selectivity towards ERα.•N, N-dialkylamino side chain inhibited co-activators binding by changing conformation of helix-12. Drug discovery and development have gained momentum due to the rational drug design by engaging computational tools and bioinformatics methodologies. Bioisosteric replacements and hybrid molecular approaches are the other inventive processes, used by medicinal chemists for the desired modifications of leads for clinical drug candidates. SERMs, ought to produce inhibitory activity in breast, uterus and agonist activity in other tissues, are beneficial for estrogen-like actions. ER subtypes α and β are hormone dependent modulators of intracellular signaling and gene expression, and development of ER selective ligands could be an effective approach for treatment of breast cancer. This report has critically investigated the possible designing considerations of SERMs, their in silico interactions, and potent pharmacophore generation approaches viz. indole, restricted benzothiophene [3, 2-b] indole, carborane, xanthendione, combretastatin A-4, organometallic heterocycles, OBHS-SAHA hybrids, benzopyranones, tetrahydroisoquinolines, Dig G derivatives and their specifications in drug design and development, to rationally improve the understanding in drug discovery. This also includes various strategies for the development of dual inhibitors for the management of antiestrogenic resistance.