VIRTUAL DESIGN OF NOVEL OF ORALLY BIOAVAILABLE PIPERAZINE INHIBITORS OF ENOYL-ACYL CARRIER PROTEIN REDUCTASE OF MYCOBACTERIUM TUBERCULOSIS WITH FAVORABLE PHARMACOKINETIC PROFILES

Koffi Charles Kouman; Afﬁba Florance Kouassi; Yves Kily Hervé Fagnidi; Issouf Fofana; Koffi N’Guessan Placide Gabin Allangba; Mélalie Kéïta; Eugene Megnassan

doi:10.22270/ujpr.v9i5.1216

Koffi Charles Kouman Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast.
Afﬁba Florance Kouassi Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast.
Yves Kily Hervé Fagnidi Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast. Science and Technology Training and Research Unit, Alassane Ouattara University, Ivory Coast.
Issouf Fofana Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast.
Koffi N’Guessan Placide Gabin Allangba Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast. Laboratoryof Environmental Sciences and technologies, Jean Lorougnon Guédé University, Ivory Coast. Laboratory of Biophysics and Nuclear Medicine (LBNM), Félix Houphouët-Boigny University, Ivory Coast. Department of Medical Physics, University of Trieste and International Centre for Theoretical Physics (ICTP), Trieste, Italy.
Mélalie Kéïta Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast.
Eugene Megnassan Applied Fundamental Physics Laboratory (LPFA), Nangui Abrogoua University, Ivory Coast. Laboratory of Structural and Theoretical Organic Chemistry, Félix Houphouët-Boigny University, Ivory Coast. International Center for Theoretical Physics, ICTP-UNESCO, Coastal Road 11, I-34151 Trieste, Italy. International center for applied research and sustainable technology, SK-84104 Bratislava. Laboratory of Crystallography-Molecular Physics, Félix Houphouët-Boigny University, Ivory Coast.

10.22270/ujpr.v9i5.1216

Keywords:

ADME, InhA inhibitors, Piperazine, pharmacophore, QSAR, tuberculosis, virtual screening

Abstract

Background: Drug-resistant strains have been a real problem for anti-tuberculosis therapies in recent decades. Here we elaborated the virtual rational design and evaluation of a novel class of piperazine (PPZ) analogs as InhA-Mt inhibitors with a favorable pharmacokinetic profile.

Method: By in situ modification of the crystal structure of InhA-PPZ1 (Protein Data Bank (PDB) entry code: 1P44), which is the reference structure of a test set of 12 PPZs with their known inhibitory potencies experimental data (IC₅₀^exp), we prepared three-dimensional (3D) models of Inha-PPZx complexes. A structure activity relationship (SQR) model was built in the gas phase in the search for active conformations of PPZ 1-12 linearly correlating the calculated enthalpy of formation of the InhA-PPZ complex and thepIC₅₀^exp. Finally Lipinski's rule of 5 was used to filter the VCL which was subsequently screened by the pharmacophore model. The predicted activities of the new PPZ analogs obtained were evaluated with the initial QSAR and their pharmacokinetic profile was also evaluated.

Results: The virtual combinatorial library of more than 310,550 PPZ analogs was filtered by Lipinski's rule until it reached 19,044 analogs. Virtual screening by the pharmacophore made it possible to select 50 potential new analogues with predicted inhibitory potencies up to 100 times better than that of PPZ1 (IC₅₀^exp=160 nM). The predicted pharmacokinetic properties of the new analogues showed high cell membrane permeability, side effects and high human oral absorption compared to current anti-TB candidates.

Conclusions: The combined use of molecular modeling and PH4 in virtual screening makes it possible to propose new powerful anti-tuberculosis drugs with favorable pharmacokinetic profiles.