In-silico discovery of efficient second-generation drug derivatives with enhanced antihistamine potency and selectivity

Abstract

The current study focuses on the potential of second-generation antihistamines, which exhibit fewer side effects compared to first-generation drugs, to block the Histamine H₁ receptor (H₁R) and mitigate allergic responses. We screened several derivatives of second-generation drugs taking Desloratadine (Deslo) and Acrivastine (Acra) as seed compounds. We performed molecular docking, drug-likeness, quantum chemical calculations, UV–visible and infrared spectroscopy, molecular electrostatic potential (MEP) mapping for understanding drug derivatives potential as efficient drugs and molecular dynamics (MD). The results depicted that among all Deslo1 showed best binding energy of −8.6 kcal/mol and best inhibition constant too. Moreover, LEU157 formed a conventional hydrogen bond with a ligand at distance of 2.51 Å in Deslo1. Deslo2 showed 95.2 % intestinal absorption which is quite good. None of the drugs showed any toxicity. The residues from catalytic site like Phe 116, Leu 154 and Leu 157 showed reasonably small fluctuations owing to their interactions with respective ligands. The RMSDs of Acra1 and Deslo2 mostly stay within 1Å range. For MD simulations best docked compounds (Acra1, Acra2, Deslo1 and Deslo2) were chosen and carried for 120 ns (120 ×10⁶ fs). MD simulations trajectory is analyzed for the assessment of some important parameters like RMSD, RMSF, SASA, and RG. Moreover, ADMET analysis are performed to confirm their drug-like properties. The molecular geometries of Acra2 are optimized in gas phase as well as water solvent environments to simulate aqueous like conditions for optimized geometries. Significant differences are observed in the bond lengths and angles especially for polar functional groups, due to the solvation of hydrogen-bond donors and acceptors. The current study identify new therapeutic candidates for managing allergic rhinitis, which may evoke the scientific interests of scientists through in-vivo testing of hit drugs that were not explored previously.