A new de novo drug design procedure, applicable in the circumstances of scarcity of experimental data, is proposed. The proposed method integrates de novo and fragment-based drug design approaches. This protocol is uncomplicated, uses openly available resources and can be used to design new molecules that would inhibit the newly discovered or under researched targets. The new potential inhibitors are modelled based on energy minima of small molecules in the binding site. The designed structures are modified following an in-house developed, unambiguous algorithm. These modifications improve predicted binding affinities and pharmacokinetic properties of the designed compounds. The suitability of the proposed drug design approach is confirmed by molecular dynamics simulations, and analysis of both binding modes and binding energies of drug candidates (calculated using MM/PBSA method). Lastly, alternative retrosynthetic approaches to the drug candidates are proposed.Communicated by Ramaswamy H. Sarma.
Keywords: ADME; de novo; drug design; emerging diseases; neglected diseases.