arXiv subjects

Amit Kadan

Publications and source records attributed to Amit Kadan.

3 recordsLinked to original sources

arXiv2024

Guided Multi-objective Generative AI to Enhance Structure-based Drug Design

Generative AI has the potential to revolutionize drug discovery. Yet, despite recent advances in deep learning, existing models cannot generate molecules that satisfy all desired physicochemical properties. Herein, we describe IDOLpro, a generative chemistry AI combining diffusion with multi-objective optimization for structure-based drug design. Differentiable scoring functions guide the latent variables of the diffusion model to explore uncharted chemical space and generate novel ligands in silico, optimizing a plurality of target physicochemical properties. We demonstrate our platform's effectiveness by generating ligands with optimized binding affinity and synthetic accessibility on two benchmark sets. IDOLpro produces ligands with binding affinities over 10%-20% better than the next best state-of-the-art method on each test set, producing more drug-like molecules with generally better synthetic accessibility scores than other methods. We do a head-to-head comparison of IDOLpro against a classic virtual screen of a large database of drug-like molecules. We show that IDOLpro can generate molecules for a range of important disease-related targets with better binding affinity and synthetic accessibility than any molecule found in the virtual screen while being over 100x faster and less expensive to run. On a test set of experimental complexes, IDOLpro is the first to produce molecules with better binding affinities than experimentally observed ligands. IDOLpro can accommodate other scoring functions (e.g. ADME-Tox) to accelerate hit-finding, hit-to-lead, and lead optimization for drug discovery.

physics.chem-ph↗

arXiv2023

Accelerated Organic Crystal Structure Prediction with Genetic Algorithms and Machine Learning

We present a high-throughput, end-to-end pipeline for organic crystal structure prediction (CSP) -- the problem of identifying the stable crystal structures that will form from a given molecule based only on its molecular composition. Our tool uses Neural Network Potentials (NNPs) to allow for efficient screening and structural relaxations of generated crystal candidates. Our pipeline consists of two distinct stages -- random search, whereby crystal candidates are randomly generated and screened, and optimization, where a genetic algorithm (GA) optimizes this screened population. We assess the performance of each stage of our pipeline on 21 molecules taken from the Cambridge Crystallographic Data Centre's CSP blind tests. We show that random search alone yields matches for $\approx 50\%$ of targets. We then validate the potential of our full pipeline, making use of the GA to optimize the Root Mean-Squared Deviation (RMSD) between crystal candidates and the experimentally derived structure. With this approach, we are able to find matches for $\approx80\%$ of candidates with 10-100 times smaller initial population sizes than when using random search. Lastly, we run our full pipeline with an ANI model that is trained on a small dataset of molecules extracted from crystal structures in the Cambridge Structural Database, generating $\approx 60\%$ of targets. By leveraging ML models trained to predict energies at the DFT level, our pipeline has the potential to approach the accuracy of \emph{ab initio} methods and the efficiency of empirical force-fields.

cond-mat.mtrl-sci↗

arXiv2020

Exponential Convergence of Gradient Methods in Concave Network Zero-sum Games

Motivated by Generative Adversarial Networks, we study the computation of Nash equilibrium in concave network zero-sum games (NZSGs), a multiplayer generalization of two-player zero-sum games first proposed with linear payoffs. Extending previous results, we show that various game theoretic properties of convex-concave two-player zero-sum games are preserved in this generalization. We then generalize last iterate convergence results obtained previously in two-player zero-sum games. We analyze convergence rates when players update their strategies using Gradient Ascent, and its variant, Optimistic Gradient Ascent, showing last iterate convergence in three settings -- when the payoffs of players are linear, strongly concave and Lipschitz, and strongly concave and smooth. We provide experimental results that support these theoretical findings.

cs.LG↗