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Trieste, Italy

Bonini C.,University of Basilicata | Chiummiento L.,University of Basilicata | Di Blasio N.,University of Basilicata | Funicello M.,University of Basilicata | And 10 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)-glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease. © 2014 Elsevier Ltd. All rights reserved. Source

Keita M.,ICS UNIDO | Keita M.,University of Abobo Adjame | Kumar A.,ICS UNIDO | Kumar A.,CSIR - Central Electrochemical Research Institute | And 13 more authors.
RSC Advances | Year: 2014

We have designed new potent inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt) using structure-based molecular design. Three-dimensional (3D) models of TMPKmt-inhibitor complexes were prepared by in situ modification of the crystal structure of TMPKmt co-crystallized with the natural substrate deoxythymidine monophosphate (dTMP) (PDB entry code: 1G3U) and a training set of 20 thymine derivatives bearing an aliphatic or aromatic group attached through a spacer (THMDs) with known inhibitory potencies. A QSAR model was elaborated for the training set THMDs and a linear correlation was established between the computed free energies of THMD binding and observed enzyme inhibition constants (Ki exp). Validation of this QSAR model was performed with 3D-QSAR pharmacophore generation (PH4). Structural information derived from the 3D model and breakdown of computed TMPKmt-THMDs interaction energies up to individual active site residue contributions helped us to design new more potent TMPKmt inhibitors. We obtained a reasonable agreement between the free energies of TMPKmt-THMDs complexation (ΔΔGcom) and Ki exp values, which explained approximately 93% of the TMPKmt inhibition data (pKi = -0.1422 ΔΔGcom + 4.9199, R2 = 0.93). Similar agreement was established for the PH4 pharmacophore model (pKi exp = 1.0016 × pKi pre + 0.0077, R2 = 0.95). Comparative analysis of the active site residue contributions directed substitutions to various positions of the naphtholactam or naphthosultam moeties and suggested their replacement with phthalimido or isoindolinone or indanone rings, which led to a predicted increase of the inhibitory potency. The predicted Ki pre for the best inhibitor candidate reached the picomolar range for aliphatic acyclic nucleoside analogs and for benzyl pyrimidine-like analogs. This computational approach, which combines molecular modelling, pharmacophore generation and analysis of TMPKmt-THMDs interaction energies resulted in a set of proposed TMPKmt inhibitors. It can thus direct medicinal chemists in their search for new antituberculotic agents. © The Royal Society of Chemistry 2014. Source

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