Seminar : Dr. Neha Tripathi

Abstract (pdf)

Dr. Neha Tripathi
CEISAM UMR 6230
UFR des Sciences et des Techniques, Université de Nantes (France)
Corresponding author: Adèle D. LAURENT - Adele.Laurent@univ-nantes.fr

The drug discovery cycle is a long, time consuming and a costly process. Computer aided drug design (CADD) has
occupied an important position in the drug discovery pipeline due to its successful application in the identification of
several drugs (e.g. captopril, dorzolamide, aliskiren) [1,2]. In this lecture, we will take you through the journey to the
general introduction and importance of various basic techniques of CADD. In the end we will discuss two exciting
case studies which encapsulate the application of these techniques.
(i) The first case study is based on the enzyme phospholipase C gamma 1 (PLCγ1), which is a potential drug target
for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. In this
work, a systematic virtual screening protocol is adopted to identify novel inhibitors against the PLCγ1. An in-depth
biophysical analysis provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular
docking, and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising
inhibitors, all characterized by a stable binding with PLCγ1 and a comparable or higher binding affinity to ritonavir
(DGbind ≤ -25 kcal/mol), one of the most potent inhibitor reported till now [3].
(ii) The second case study is about the structural exploration of human granzyme B (hGzmB), an executive
component of perforin/granzyme mediated apoptotic pathway. In this work, long classical molecular dynamics (MD)
simulations are employed to systematically analyze the structural dynamics of hGzmB in the interconversion of active
and inactive conformation. Based on these observations a chain of intramolecular interactions was proposed to be
responsible for the conformational dynamics in hGzmB. The proposed mechanism was also supported from in silico
mutational studies, where Arg216Ala mutation resulted into the failure of substrate binding. This critical
understanding of hGzmB activation at the atomic level is of prime importance for the identification of hGzmB
modulating agents, by guided tailoring of structural features in therapeutic agents [4,5].
[1]. Expert Opin. Drug Discov. 2006, 1, 103 [2]. Annu Rev. Biophys Biomol. Struct. 1998, 27, 249 [3]. Int. J. Mol. Sci.
2019, 20, 4721 [4]. Front. Immunol. 2013, 4, 497 [5]. Allergy 2014, 69, 1454.