Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Computer-aided Design of Peptidomimetic Inhibitors of falcipain-3: QSAR and Pharmacophore Models

Boris D. Bekono
ORCID logo ,
Akori Esmel
,
Brice Dali
,
Fidele Ntie-Kang
* ,
Melalie Keita
,
Luc Calvin Owono Owono
,
Eugene Megnassan
* ORCID logo
Version 1 : Received: 12 July 2021 / Approved: 12 July 2021 / Online: 12 July 2021 (14:48:13 CEST)

A peer-reviewed article of this Preprint also exists.

Bekono, B.D.; Esmel, A.E.; Dali, B.; Ntie-Kang, F.; Keita, M.; Owono, L.C.O.; Megnassan, E. Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models. Sci. Pharm. 2021, 89, 44. Bekono, B.D.; Esmel, A.E.; Dali, B.; Ntie-Kang, F.; Keita, M.; Owono, L.C.O.; Megnassan, E. Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models. Sci. Pharm. 2021, 89, 44.

Abstract

In this work antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) have been proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (IC50exp) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure-activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔGcomp) and the experimentally measured IC50exp: (pIC50exp=-(IC50exp/109) =-0.4517×∆∆Gcomp+4.0865 ; R2 = 0.89). Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogs where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictory inhibitory activities falling within the low nanomolar concentration range.

Keywords

drug design; falcipain; malaria; peptidomimetics; Plasmodium falciparum; virtual screening; pharmacophore.

Subject

Chemistry and Materials Science, Analytical Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.