Abstract:
Viruses are known for their extremely high mutation rates, allowing them to evade both the human immune system and many forms of standard medicine. Despite this, the RNA dependent RNA polymerase (RdRp) of the RNA viruses has been largely conserved, and any significant mutation of this protein is unlikely. The recent COVID-19 pandemic presents a need for therapeutics. We have designed a de novo drug design algorithm that generates strong binding ligands from scratch, based on only the structure of the target protein’s receptor. In this paper, we applied our method to target SARS-CoV-2 RdRp and generated several de novo molecules. We then chose some drug molecules based on the structural similarity to some of our strongest binding de novo molecules. Subsequently, we showed, using rigorous all-atom explicit-water free energy calculations in near-microsecond time scales using state-of-the-art well-tempered metadynamics simulations, that some of our de novo generated ligands bind more strongly to RdRp than the recent FDA approved drug remdesivir in its active form, remdesivir triphosphate (RTP). We elucidated the binding mechanism for some of the top binders and compared it with RTP. We believe that this work will be useful both by presenting lead structures for RdRp inhibition and by delivering key insights into the residues of the protein potentially involved in the binding/unbinding of these small molecule drugs, leading to more targeted studies in the future.