In Silico Evaluation of Bioactive Compounds of Citrullus lanatus as Potential Noncovalent KRAS Inhibitors in the Treatment of Human Cancer

Cancer deaths and other dangerous symptoms associated with it make the search for therapies to combat it a necessity. The use of drugs has been implicated in some debilitating side effects, this makes scientists to look for safer, cheaper, and more effective alternatives. One of such ways is the use of plants/fruits that are rich in bioactive components. Citrullus lanatus is one plant that is grown in almost every part of the world and rich in bioactive secondary metabolites. Kirsten rat sarcoma virus is a very popular oncogene in human tumours that has been targeted in the search for anticancer drugs. This work therefore screened the phytochemicals in Citrullus lanatus against a KRAS receptor via molecular docking. The hit compounds and the co-crystallized ligand of the receptor were subjected to molecular dynamic simulation to determine their stability, modelled and optimized at the DFT/B3LYP/6-311G(d,p) level of theory and also screened for their drug-likeness and ADMET properties. Extra-precision docking revealed that ( ±)-Taxiforin (-7.23 kcalmol⁻¹), (E)-Coniferin (-6.31 kcalmol⁻¹) and Isorhamnetin (-5.71 kcalmol⁻¹) displayed better docking scores than the reference compound (-5.07 kcalmol⁻¹). Molecular dynamics simulation reveals the stability of KRAS-ligand complexes. The molecules have sites to interact with biological systems, as revealed by the DFT results. Pharmacokinetics and drug-likeness revealed that the molecules are promising and safe. Citrullus lanatus should be encouraged for consumption, while the hit compounds should be subjected to further pre-clinical and clinical investigations.