Design of a Structurally Novel Multipotent Drug Candidate by the Scaffold Architecture Technique for ACE-II, NSP15, and Mpro Protein Inhibition: Identification and Isolation of a Natural Product to Prevent the Severity of Future Variants of Covid 19 and a Colorectal Anticancer Drug.

Abstract

Scaffold architecture in the sectors of biotechnology and drug discovery research include scaffold hopping and molecular modelling techniques and helps in searching for potential drug candidates containing different core structures using computer-based software, which greatly aids medicinal and pharmaceutical chemistry. Going ahead, the computational method of scaffold architecture is thought to produce new scaffolds, and the method is capable of helping search engines toward producing new scaffolds that are likely to represent potent compounds with high therapeutic applications, which is a possibility in this case as well. Here we probate a different interactive design by natural product hopping, molecular modelling, pharmacophore modelling, modification, and combination of the phytoconstituents present in different medicinal plants for developing a pharmacophore-guided good drug candidate for the variants of SARS-CoV-2 or Covid 19. In the modern era, these approaches are carried out at every level of development of scaffold queries, which are increasingly summarized from chemical structures. In this context, we report on a successfully designed drug-like candidate having a high-binding-affinity “compound SLP” by understanding the relationships between the compounds’ pharmacophores, scaffold functional groups, and biological activities beyond their individual applications that abide by Lipinski’s rule of five, Ghose rule, Veber rule etc. The new scaffold generated by altering the core of the known phyto-compounds holds a good predicted ADMET profile and is examined with iMODS server to check the molecular dynamics simulation with normal mode analysis (NMA). The scaffold’s three-dimensional (3D) structure yields a searchable natural product koenimbine from a conformer database having good ADMET property and high availability in spice Murraya koenigii leaves. M. koenigii leaves are easily available in the market, and might ensure the immunity, good health, and well-being of people if affected with any of the variants of Covid 19. The cell viability studies of koenimbine on murine colorectal carcinoma cell line (CT-26) showed no toxicity on normal mice lymphocyte cells (MLCs). The anticancer mechanism of koenimbine was displayed by its enhanced capacity to produce intercellular reactive oxygen species (ROS) in the colorectal carcinoma cell line.