Исследование сродства альдонамидов к рецепторам KASA в контексте разработки противотуберкулезных препаратов

Abstract

Для соответствующих пентозам и гексозам альдонамидов и их амино-аналогов установлена in silico зависимость строение — биологическая активность (влияние природы функциональной группы и относительной конфигурации). Так, длина углеродного скелета, относительная конфигурация всех стереогенных центров и природа терминальной группы влияют на сродство лиганда с рецептором. Наибольшие энергии связывания были выявлены для альтронамидов и гюконамидов (например, значения ∆G = –10,93 для N-третбутил-L-альтронамида; ∆G = –11,48 для N-бензил-L-альтронамида). Предполагаемый фармакофор содержит шестиуглеродный скелет с L-альтро- или D-глюко- конфигурацией скелета, с терминальной гидрофобной N-бензил- или N-бензиламидной группой, а также аминогруппой у 4 атома углерода для альтро-конфигурации.

The series of more than 50 open-chain aldonamides in context of the influence of their relative configuration and functionality on affinity to KasA receptor have been studied. The receptor choice (2WGF Transferase: chain A) is based on the comparison of SAR obtained both in silico and in vitro experiments for free-hydroxy and acylated isonipecotamides synthesized previously. To design open-chain derivatives we have chosen monose derivatives which are structurally and functionally isosteric to isonipecotamides and possessing all possible relative configurations. Structure design includes monose skeleton modification by introduction of the substituted amide and amino groups (both transformations are available from the classical sugar chemistry). The in silico study was carried out by using the semi-empirical PM6 and the MMFF94 geometric optimization techniques for pH=7. To find the energetically optimal conformations for labile open-chain aldonamides we have proceeded every docking for at least 100 runs. L-altro- and D-gluco- configuration-based derivatives showed the highest affinity to receptor. After variation of substituents in amide fragment and replacement of hydroxyl with amino group we have found the highest affinity for N-tert-butyl L-4-deoxy-4-aminoaltrosamide (–10.93 kcal / mol) and N-benzyl D-gluconamide (–11.48 kcal / mol). The SAR analysis showed these structures form conformations with the maximum number and the optimal geometry of intramolecular hydrogen bonds, as well as hydrophobic interactions. The latter can be discussed in terms of multiple interactions between N-alkyl substituted amide group and protein hydrophobic side chains (Pro and Ile in protein studied). Based on the data obtained, a pharmacophore was proposed with the L-altro- or D-gluco- configuration, bulky hydrophobic N-substituted amide group and possible amino group at 4 th C-Carbon.