Seminar on the topic: Computational and Synthetic Advances in Drug Discovery

At 2:30 p.m., August 8, 2025, IAST organized an academic exchange session at the Library's 5th floor meeting room with detailed content as follows:

1/ PhD. Binh Khanh Mai reported on the topic "Computational Studies of Stereoselective Biocatalysis"

Abstract:  

Owing to their exquisite control over reaction stereochemistry, biocatalytic methods have recently emerged as an appealing strategy for stereoselective chemical functionalization. However, due to the lack of theoretical understanding of the complex nature of enzyme–substrate interactions, understanding the origin of enantioselectivity in enzymatic transformations is not trivial. Another potential complexity in understanding enantiocontrol of enzymatic functionalization is the identity of the selectivity-determining step. To address these challenges, we conducted a series of computational investigations employing density functional theory (DFT), QM/MM calculations, classical and ab initio molecular dynamics (MD), and metadynamics simulations to elucidate reaction mechanisms and rate determination steps. Furthermore, we performed in-depth analyzes—such as energy decomposition analysis (EDA) and non-covalent interaction (NCI) analysis—to uncover key factors governing selectivity, the influence of conformational dynamics, and the role of steric environments. Ultimately, my goal is to shift enzyme design from an empirical, trial-and-error process toward a more rational and predictive approach driven by computational insights.

2/ PhD. Kowit Hengphasatporn reports on the topic "PaCS-Q: Tools for Path Sampling in QM/MM MD for Complex Enzymatic Mechanisms"

Abstract: 

Elucidating enzymatic reaction mechanisms is essential for rational drug design and optimization catalyst. Although QM/MM molecular dynamics (MD) simulations provide atomic insight into bond-breaking and bond-forming events, their application is constrained by high computational cost and limited timescales. To address these challenges, we introduce PaCS-Q, an enhanced sampling approach in MD and QM/MM MD simulation that accelerates reaction pathway discovery without relying on predefined reaction coordinates or external restraints. PaCS-Q enables time-resolved sampling of key mechanistic steps and efficiently identifies transition states and intermediates. By capturing both stepwise and concerted mechanisms with high accuracy and significantly reduced computational cost, PaCS-Q offers a powerful tool for advancing enzyme-targeted drug discovery.

3/ PhD. Nguyen Trung Hai reported on the topic "Computational Techniques for Accurate Protein-Ligand Binding Free Energy Estimation"
Abstract:

 In the fields of drug discovery and molecular biology, understanding protein-ligand interactions is crucial for elucidating biochemical pathways and designing therapeutic agents. In this I will discuss my research on the theoretical development  of accurate and computationally efficient estimators for protein-ligand binding free energy based on simulation data obtained from enhanced sampling methods such as replica exchange.The applications of these estimators on some biomolecular targets will be demonstrated. Alongside physics-based computational approaches, I will also delve into recent developments in knowledge-based methods that leverage experimental data. These include Bayesian techniques for inferring binding free energy from Isothermal Titration Calorimetry (ITC) data and machine learning models that are trained using experimental binding affinity data to predict binding free energy with high accuracy.

4/ PhD. Truong Ngoc Hung reported on the topic "Synthesis and in vitro anti-cancer activity of new hybrid derivatives between artemisinin and nucleobases"
Abstract: 

This study reports the results for synthesis of some new hybrid derivatives between artemisinin and esters of AZT (zidovudine) via N-alkylation with bromoethoxy ether of DHA as the intermediate. In the first step, the intermediate bromoethoxy ether of DHA is prepared using the O-alkylation of DHA with bromoethanol in CH2Cl2 at low temperature with BF3-Et2O as catalyst. The next step is the N-alkylation between the obtained intermediate with esters of AZT in DMF at room temperature using alkaline catalyst K2CO3 to give new hybrid derivatives between artemisinin and esters of AZT in good yields (68-74%). The synthesized new derivatives are structurally elucidated by NMR and HRMS spectral data. Additionally, in vitro cytotoxic activity of these derivatives of artemisinin are screened and evaluated against human cancer cell lines.