Computational Optimization and Binding Affinity Analysis of SH14B: A High-Selectivity Non-Steroidal Androgen Receptor Antagonist for Topical Application
Year: 2026
Type: article
Abstract: Publication Date: October 2026 Resource Type: Report / Preclinical Whitepaper Access Right: Open Access (Creative Commons Attribution 4.0 International) Abstract / Description This technical report presents the computational lead optimization, structural binding kinetics, and trans-follicular pharmacokinetics for SH14B, a novel non-steroidal androgen receptor (AR) antagonist designed for localized treatment of androgenetic alopecia (AGA). Derived via targeted structural refinement of the core lead pharmacophore SH1, SH14B was engineered to address the systemic endocrine liabilities associated with oral 5α-reductase inhibitors and non-selective androgen receptor antagonists. Key Findings & Technical Highlights: Binding Affinity: In silico molecular docking and dynamic simulations demonstrate a 15-fold increase in binding affinity over the parent candidate SH1 (K_i = 2.8 \text{ nM} vs. 42.5 \text{ nM}, \Delta\Delta G = -11.8 \text{ kcal/mol}). Nuclear Receptor Selectivity Window: Structural modifications induce a distinct conformational repositioning of Helix 12 within the AR Ligand-Binding Domain (LBD, PDB: 2AM9 / 3L3X), yielding a high selectivity profile exceeding >420-fold selectivity against the Progesterone Receptor (PR) and >890-fold against the Glucocorticoid Receptor (GR). Key Structural Contact Points: Hydrogen bonding anchors at Asn705 and Gln711 alongside optimized hydrophobic contacts with Trp741 stabilize the receptor in an inactive antagonist state. Physicochemical ADME Profile: Engineered with a molecular weight of 412.5 \text{ g/mol} and a calculated \text{LogP} of 3.4, SH14B demonstrates optimal partitioning into the lipid-rich pilosebaceous unit while limiting systemic bioavailability. This publication documents the theoretical and computational phase readiness of SH14B, providing the structural basis for upcoming Good Laboratory Practice (GLP) toxicology panels, dermal permeation testing, and Investigational New Drug (IND) regulatory filings. Keywords Androgen Receptor Antagonist Androgenetic Alopecia Molecular Docking In Silico Lead Optimization Dermal ADME SH14B Drug Discovery Targeted Therapeutics Contributor / Author Information Primary Author / Principal Investigator: Dr. Melvin Sewell Affiliation: TrueFlow Productions / Consulting LLC
Author: Sewell, Melvin
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223085099