Series of Novel Integrastatins Analogues: In silico Study of Physicochemical and Bioactivity Parameters

Integrastatins are naturally occurring heterotetracyclic compounds with a broad spectrum of biological activity. A number of new structural analogues of integrastatins 2a-u have been synthesized using a novel one-step method [1], but a systematic theoretical study of their structural features and biological activity has not been realized. This study aimed to in silico investigate physicochemical and bioactivity properties for a series of 21 new synthetic analogues of natural integrastatins. Global chemical reactivity descriptors was assessed using DFT B3LYP 6-311++G(d, p) CPCM (solvent — water) calculations. High ionization potential IP in the range from 5.9 to 7.1 eV and electron affinity EA at the level of 2.1 to 3.2 eV were shown, which together with a sufficiently large energy gap DEgap from 3.8 to 4.6 eV indicates the hard nature of the compounds 2a-u. Antiviral activity and inhibitory potential as CYP2C19 inducers were identified using the PASSOnline resource. According to the results of molecular docking studies Human immunodeficiency virus HIV-1 reverse transcriptase protein (PDB ID: 3V81) and protein of the RNA-dependent RNA polymerase of the SARS-CoV-2 (PDB ID: 7AAP) can serve as a likely biological target for the compounds 2a-u. Potentially high oral efficacy and a promising safety profile for the therapeutic use were showed using ADMETlab 3.0 online portal. Further experimental in vitro and in vivo studies of the pharmaceutical potential of compounds 2a-u is need for more accurate evaluation the assumptions made on the basis of in silico approach.