Biology subjects

Gurram, K.

Publications and source records attributed to Gurram, K..

3 recordsLinked to original sources

bioRxiv2023

PROTAC-Design-Evaluator (PRODE) -- An Advanced Method for in-silico PROTAC design

PROTAC (proteolysis-targeting chimeras) is a rapidly evolving technology to target undruggable targets. The mechanism by which this happens is when a bifunctional molecule binds to a target protein and also brings in proximity an E3 ubiquitin ligase to trigger ubiquitination and degradation of the target protein. Yet in-silico driven approaches to design these hetero-bifunctional molecules that have the desired functional properties to induce proximity between the target protein and E3 ligase remains to be established. In this paper we present a novel in-silico method for PROTAC design and to demonstrate the validity of our approach. We show that for a BRD4-VHL PROTAC ternary complex known in the literature, we are able to reproduce the PROTAC binding mode, the structure of ternary complex formed therein and the free energy ({Delta}G) thermodynamics favoring ternary complexation through theoretical computational methodologies. Further, we demonstrate the use of Thermal Titration Molecule Dynamics (TTMD) to differentiate the stability of PROTAC mediated ternary complexes. We employ the proposed methodology to design a PROTAC for a new system of FGFR1-MDM2 to degrade the FGFR1 (Fibroblast growth factor receptor 1) which is overexpressed in cancer. Our work presented here and named as PROTAC-Designer-Evaluator (PRODE) contributes to the growing literature of in-silico approaches to PROTAC design and evaluation by incorporating the latest in-silico methods and demonstrates advancement over previously published PROTAC in-silico literature.

bioinformatics↗

bioRxiv2022

An in-silico approach for novel molecular glue design by rationalizing known molecular glue mediated ternary complex formation

Protein function modulation using small molecule binding is an important therapeutic strategy for many diseases. However, many proteins remain undruggable due to lack of suitable binding pockets for small molecule binding. Proximity induced protein degradation using molecular glues has recently been identified as in important strategy to target the undruggable proteins. Molecular glues were discovered serendipitously and as such currently lack an established approach for in-silico design rationale. In this work, we attempt to establish the rationale for a known case and having inferred the rationale, we discuss how the rationale can be applied in-silico to design novel molecular glue through AI powered techniques. We believe the establishing of in-silico rationale for molecular glue design would be a valuable and welcome addition to the literature to further accelerate the discovery of molecular glues to drug undruggable targets.

bioinformatics↗

bioRxiv2022

A New In-Silico Approach for PROTAC Design and Quantitative Rationalization of PROTAC mediated Ternary Complex Formation

Proteolysis-Targeting Chimeric Molecules (PROTAC) is a rapidly emerging technology for drug target protein degradation and drugging undruggable drug targets. There is a growing literature on in-silico approaches to the complex problem of PROTAC design, specifically the advantages of AI/ in-silico methods in the PROTAC Design Make Test Analyze (DMTA) cycle. Our work presented here aims to contribute to the growing literature of in-silico approaches to PROTAC design by incorporating and demonstrating incremental advancement over previously published methods. We use AI based generative methods for PRTOAC design and Molecular Dynamics to evaluate the stability of the ternary complex formed and ability of the PROTAC to hold the target protein and E3 ligase together stably. To quantify the performance of the PROTAC candidate, we also estimate computationally the PROTAC performance metrics routinely measured by the experimentalists in PROTAC assays. We use highly accurate absolute binding free energy calculations used traditionally in protein-ligand space for the PROTAC system. We calculate (Gibbs free energy change) {Delta}G for binary complex formation and ternary complex formation mediated by the PROTAC using Free Energy Perturbation - Thermodynamics Integration (FEP-TI) method which is benchmarked in literature with a root mean square error of 0.8 kcal/mol. We calculate {Delta}G for ternary and binary complexes and estimate whether {Delta}G for ternary is lower than the {Delta}G estimated for binary complexes. When the {Delta}G for ternary is lower than the binary it is inferred that ternary complexation is favoured over binary. Therefore, through these methods we can theoretical estimate {Delta}G measured by experimentalists in PROTAC assays such as Isothermal titration calorimetry (ITC) and Surface plasmon resonance (SPR) which capture the {Delta}G for ternary and binary complex formation mediated by the PROTAC. This method will help reduce time as well as costs of the PROTAC DMTA cycle and will accelerate early stage PROTAC drug discovery. As an illustrative application of our in-silico PROTAC design approach, we chose the target Fibroblast growth factor receptor 1(FGFR-1) which is a target approved drug for colorectal cancer. We report the findings and conclude with future research directions.

bioinformatics↗