We have found at least five molecules having stronger binding affinity than RTP (free energy < -7.1 kcal/mol). The strongest binding molecule, 43_16(named as per an internal nomenclature of our program), is found to have a free energy value of -11.8 kcal/mol. The free energy surface of 43_16 with minimum free energy path to unbound state (black dotted lines) and relevant intermediate states (states I to VI) is shown in the Fig. . The major contribution to the free-energetic stability of 43_16 is from hydrophobic stabilizing interactions (from the protein residues Arg836, Ser814, Ser759, and Gln815) and hydrogen bonding interactions (from protein residues Asp865 and Lys593) as shown in A bar plot showing the free energy of binding of all validated molecules by our simulation protocol is shown in Fig. . Other molecules with better binding affinity include Telcagepant and Dihydroergotamine (present-day drugs), and 40_73 and 43_2 (generated de-novo) with free energy values -10.6 kcal/mol, -10.1 kcal/mol, -8.7 kcal/mol, and -8.1 kcal/mol in that order. The free energy surfaces of these molecules are represented in the Fig. , along with the chemical structure of the molecules. The free energy surface of all others with lesser binding affinity than RTP is shown in Fig. of the Supporting Information.