AE and PCA ( unit norm ).py

import os
import numpy as np
from rdkit import Chem
from rdkit.Chem import Draw, Descriptors
from matplotlib import pyplot as plt
import pandas as pd
from sklearn.model_selection import train_test_split
from numpy.random import seed
from tf import set_random_seed
import sklearn
from sklearn import datasets
from sklearn.preprocessing import StandardScaler, MinMaxScaler
from sklearn import decomposition
import scipy
import tensorflow as tf
from keras.models import Model, load_model
from keras.layers import Input, Dense, Layer, InputSpec
from keras.callbacks import ModelCheckpoint, TensorBoard
from keras import regularizers, activations, initializers, constraints, Sequential
from keras import backend as K
from keras.constraints import UnitNorm, Constraint
from keras.models import Model
from keras.layers import Input
from keras.layers import LSTM
from keras.layers import Dense
from keras.layers import Concatenate
from keras import regularizers

class WeightsOrthogonalityConstraint (Constraint):
    def __init__(self, encoding_dim, weightage = 1.0, axis = 0):
        self.encoding_dim = encoding_dim
        self.weightage = weightage
        self.axis = axis
        
    def weights_orthogonality(self, w):
        if(self.axis==1):
            w = K.transpose(w)
        if(self.encoding_dim > 1):
            m = K.dot(K.transpose(w), w) - K.eye(self.encoding_dim)
            return self.weightage * K.sqrt(K.sum(K.square(m)))
        else:
            m = K.sum(w ** 2) - 1.
            return m

    def __call__(self, w):
        return self.weights_orthogonality(w)

'''
smifile = 'Data\chembl_smiles.txt'
data = pd.read_csv(smifile, delimiter="\t", names=["SMILES"])
smiles_train, smiles_test = train_test_split(data["SMILES"], random_state=42)
print(smiles_train.shape)
print(smiles_test.shape)'''

data = pd.read_csv('Data\SARS-Cov.csv',names=["PUBCHEM_CID","SMILES","FOLD","PUBCHEM_ACTIVITY_OUTCOME_ASY0","PUBCHEM_ACTIVITY_OUTCOME_ASY1","PUBCHEM_ACTIVITY_OUTCOME_ASY2","PUBCHEM_ACTIVITY_OUTCOME_ASY3"])  
print(data["SMILES"])
smiles_train, smiles_test = train_test_split(data["SMILES"], random_state=42)
print(smiles_train.shape)
print(smiles_test.shape)

charset = set("".join(list(data.SMILES))+"!E")
char_to_int = dict((c,i) for i,c in enumerate(charset))
int_to_char = dict((i,c) for i,c in enumerate(charset))
embed = max([len(smile) for smile in data.SMILES]) + 5


charset = set("".join(list(data.SMILES))+"!E")
char_to_int = dict((c,i) for i,c in enumerate(charset))
int_to_char = dict((i,c) for i,c in enumerate(charset))
embed = max([len(smile) for smile in data.SMILES]) + 5


def vectorize(smiles):
    one_hot = np.zeros((smiles.shape[0], embed, len(charset)), dtype=np.int8)
    for i, smile in enumerate(smiles):
        # encode the startchar
        one_hot[i, 0, char_to_int["!"]] = 1
        # encode the rest of the chars
        for j, c in enumerate(smile):
            one_hot[i, j + 1, char_to_int[c]] = 1
        # Encode endchar
        one_hot[i, len(smile) + 1:, char_to_int["E"]] = 1
    # Return two, one for input and the other for output
    return one_hot[:, 0:-1, :], one_hot[:, 1:, :]


X_train, Y_train = vectorize(smiles_train.values)

X_test, Y_test = vectorize(smiles_test.values)
print("X",X_train.shape,X_test.shape)
input_shape = X_train.shape[1:]
print(input_shape)
output_dim = Y_train.shape[-1]
latent_dim = 64
lstm_dim = 64

unroll = False
encoder_inputs = Input(shape=input_shape)
encoder = LSTM(lstm_dim, return_state=True,
                unroll=unroll)
encoder_outputs, state_h, state_c = encoder(encoder_inputs)
states = Concatenate(axis=-1)([state_h, state_c])
neck = Dense(latent_dim, activation="relu",use_bias = True, 
                      kernel_constraint=UnitNorm(axis=0))
neck_outputs = neck(states)

decode_h = Dense(lstm_dim, activation="sigmoid")
decode_c = Dense(lstm_dim, activation="relu")
state_h_decoded =  decode_h(neck_outputs)
state_c_decoded =  decode_c(neck_outputs)
encoder_states = [state_h_decoded, state_c_decoded]
decoder_inputs = Input(shape=input_shape)
decoder_lstm = LSTM(lstm_dim,
                    return_sequences=True,
                    unroll=unroll
                   )
decoder_outputs = decoder_lstm(decoder_inputs, initial_state=encoder_states)
decoder_dense = Dense(output_dim, activation='softmax',use_bias = True, 
                      kernel_constraint=UnitNorm(axis=0))
decoder_outputs = decoder_dense(decoder_outputs)
#Define the model, that inputs the training vector for two places, and predicts one character ahead of the input
model = Model([encoder_inputs, decoder_inputs], decoder_outputs)

print (model.summary())

from keras.callbacks import History, ReduceLROnPlateau

h = History()
rlr = ReduceLROnPlateau(monitor='val_loss',metrics=['accuracy'], factor=0.5,patience=10, min_lr=0.000001, verbose=1, min_delta=1e-5)

from keras.optimizers import RMSprop, Adam

opt=Adam(lr=0.005) #Default 0.001
model.compile(optimizer=opt, loss='categorical_crossentropy',metrics=['accuracy'])

model.fit([X_train,X_train],Y_train,
                    epochs=16,
                    batch_size=256,
                    shuffle=True,
                    callbacks=[h, rlr],
                    validation_data=[[X_test,X_test],Y_test ])

import pickle
file = open('Blog_history','wb')
pickle.dump(h.history, file)

# summarize history for accuracy
plt.plot(h.history['acc'])
plt.plot(h.history['val_acc'])
plt.title('model accuracy')
plt.ylabel('accuracy')
plt.xlabel('epoch')
plt.legend(['train', 'test'], loc='upper left')
plt.show()
# summarize history for loss
plt.plot(h.history['loss'])
plt.plot(h.history['val_loss'])
plt.title('model loss')
plt.ylabel('loss')
plt.xlabel('epoch')
plt.legend(['train', 'test'], loc='upper left')
plt.show()


plt.plot(h.history["loss"], label="Loss")
plt.plot(h.history["val_loss"], label="Val_Loss")
plt.yscale("log")
plt.legend()

print(model.predict(X_train))
 

for i in range(3):
    v = model.predict([X_test[i:i+1], X_test[i:i+1]]) #Can't be done as output not necessarely 1
    idxs = np.argmax(v, axis=2)
    pred=  "".join([int_to_char[h] for h in idxs[0]])[:-1]
    idxs2 = np.argmax(X_test[i:i+1], axis=2)
    true =  "".join([int_to_char[k] for k in idxs2[0]])[1:]
    if true != pred:
        print (true, pred)
        
smiles_to_latent_model = Model(encoder_inputs, neck_outputs)
smiles_to_latent_model.save("Blog_simple_smi2lat.h5")

latent_input = Input(shape=(latent_dim,))
#reuse_layers
state_h_decoded_2 =  decode_h(latent_input)
state_c_decoded_2 =  decode_c(latent_input)
latent_to_states_model = Model(latent_input, [state_h_decoded_2, state_c_decoded_2])
latent_to_states_model.save("Blog_simple_lat2state.h5")

#Last one is special, we need to change it to stateful, and change the input shape
inf_decoder_inputs = Input(batch_shape=(1, 1, input_shape[1]))
inf_decoder_lstm = LSTM(lstm_dim,
                    return_sequences=True,
                    unroll=unroll,
                    stateful=True
                   )
inf_decoder_outputs = inf_decoder_lstm(inf_decoder_inputs)
inf_decoder_dense = Dense(output_dim, activation='softmax')
inf_decoder_outputs = inf_decoder_dense(inf_decoder_outputs)
sample_model = Model(inf_decoder_inputs, inf_decoder_outputs)

for i in range(1,3):
    sample_model.layers[i].set_weights(model.layers[i+6].get_weights())
sample_model.save("Blog_simple_samplemodel.h5")

x_latent = smiles_to_latent_model.predict(X_test)





molno = 3
latent_mol = smiles_to_latent_model.predict(X_test[molno:molno+1])
sorti = np.argsort(np.sum(np.abs(x_latent - latent_mol), axis=1))
print (sorti[0:4])
print (smiles_test.iloc[sorti[0:4]])
Draw.MolsToImage(smiles_test.iloc[sorti[1:2]].apply(Chem.MolFromSmiles))











Draw.MolsToImage(smiles_test.iloc[sorti[1:2]].apply(Chem.MolFromSmiles))
log= smiles_test.apply(Chem.MolFromSmiles)
latent_mol = smiles_to_latent_model.predict(X_test[molno:molno+1])
sorti = np.argsort(np.sum(np.abs(x_latent - latent_mol), axis=1))
print (sorti[0:2])
print (smiles_test.iloc[sorti[0:2]])
Draw.MolsToImage(smiles_test.iloc[sorti[0:2]].apply(Chem.MolFromSmiles))
Draw.MolsToImage(smiles_test.iloc[sorti[0:2]].apply(Chem.MolFromSmiles))
#logp = log.apply(Descriptors.MolLogP)

###########################################PCA
logp = smiles_test.apply(Chem.MolFromSmiles).apply(Descriptors.MolLogP)
from sklearn.decomposition import PCA
pca = PCA(n_components = 2)
red = pca.fit_transform(x_latent)
plt.figure()
plt.scatter(red[:,0], red[:,1],marker='.', c= logp)
print(pca.explained_variance_ratio_, np.sum(pca.explained_variance_ratio_))
molwt = smiles_test.apply(Chem.MolFromSmiles).apply(Descriptors.MolMR)
plt.figure()
plt.scatter(red[:,0], red[:,1],marker='.', c= molwt)

############################################################################

x_train_latent = smiles_to_latent_model.predict(X_train)
logp_train = smiles_train.apply(Chem.MolFromSmiles).apply(Descriptors.MolLogP)
from keras.models import Sequential
logp_model = Sequential()
logp_model.add(Dense(128, input_shape=(latent_dim,), activation="relu"))
logp_model.add(Dense(128, activation="relu"))
logp_model.add(Dense(1))
logp_model.compile(optimizer="adam", loss="mse")
rlr = ReduceLROnPlateau(monitor='val_loss', factor=0.5,patience=10, min_lr=0.000001, verbose=1, epsilon=1e-5)
logp_model.fit(x_train_latent, logp_train, batch_size=128, epochs=400, callbacks = [rlr])

logp_pred_train = logp_model.predict(x_train_latent)
logp_pred_test = logp_model.predict(x_latent)
plt.scatter(logp, logp_pred_test, label="Test")
plt.scatter(logp_train, logp_pred_train, label="Train")
plt.legend()

#########################################################################
def latent_to_smiles(latent):
    #decode states and set Reset the LSTM cells with them
    states = latent_to_states_model.predict(latent)
    sample_model.layers[1].reset_states(states=[states[0],states[1]])
    #Prepare the input char
    startidx = char_to_int["!"]
    samplevec = np.zeros((1,1,35))
    samplevec[0,0,startidx] = 1
    smiles = ""
    #Loop and predict next char
    for i in range(28):
        o = sample_model.predict(samplevec)
        sampleidx = np.argmax(o)
        samplechar = int_to_char[sampleidx]
        if samplechar != "E":
            smiles = smiles + int_to_char[sampleidx]
            samplevec = np.zeros((1,1,35))
            samplevec[0,0,sampleidx] = 1
        else:
            break
    return smiles
smiles = latent_to_smiles(x_latent[0:1])
print (smiles)
print (smiles_test.iloc[0])


wrong = 0
for i in range(200):
    smiles = latent_to_smiles(x_latent[i:i+1])
    mol = Chem.MolFromSmiles(smiles)
    if mol:
        pass
    else:
        print (smiles)
        wrong = wrong + 1
print ("%0.1F percent wrongly formatted smiles"%(wrong/float(1000)*100))
print ("%0.1F percent wrongly formatted smiles"%(wrong/float(1000)*100))

####### 2.9 percent wrongly formatted smiles


#Interpolation test in latent_space
i = 0
j= 2
latent1 = x_latent[j:j+1]
latent0 = x_latent[i:i+1]
mols1 = []
ratios = np.linspace(0,1,25)
for r in ratios:
    #print r
    rlatent = (1.0-r)*latent0 + r*latent1
    smiles  = latent_to_smiles(rlatent)
    mol = Chem.MolFromSmiles(smiles)
    if mol:
        mols1.append(mol)
    else:
        print (smiles)
Draw.MolsToGridImage(mols1, molsPerRow=5)