Retro-forward synthesis design and experimental validation of potent structural analogs of known drugs

Abstract

Generation of structural analogs to "parent" molecule(s) of interest remains one of the important elements of drug development. Ideally, such analogs should be synthesizable by concise and robust synthetic routes. The current work illustrates how this process can be facilitated by a computational pipeline spanning (i) diversification of the parent via substructure replacements aimed at enhancing biological activity, (ii) retrosynthesis of the thus generated "replicas" to identify substrates, (iii) forward syntheses originating from these substrates (and synthetically versatile "auxiliaries") and guided "towards" the parent, and (iv) evaluation of the candidates for target binding and other medicinal-chemical properties. This pipeline proposes syntheses of thousands of readily makeable analogs in a matter of minutes, and is deployed here to validate by experiment seven structural analogs of Ketoprofen and six analogs of Donepezil. The concise, computer-designed syntheses are confirmed in 12 out of 13 cases, offering access to several potent inhibitors. While the synthesis-design component is robust, binding affinities are predicted less accurately although still to the order-of-magnitude, which may be valuable in discerning promising from inadequate binders.